Objective and Subjective Measures of Premature Ejaculation: How Closely Do They Correspond and How Well Are the Subjective Measures Recalled?

BACKGROUND: Clinical trials evaluating new treatments for premature ejaculation (PE) should ideally include both objective end points and patient reported outcomes (PROs), but there is no consensus currently over the optimal measures or combination of outcomes. In addition, many PROs use a 1-month recall period, despite concerns about potential recall bias. AIMS: Data from a clinical trial of men with lifelong PE were used to examine the consistency of 2 core items of the Premature Ejaculation Profile (PEP), a widely used PRO for assessing subjective aspects of PE. The specific aim was to assess the level of agreement between the original 1-month recall version compared with a new event-based version of the scale in men meeting current definitions of lifelong PE. A further aim was to investigate the convergent validity between an objective end point of intravaginal ejaculatory latency time (IELT), subjective PEP responses, and a patient's Clinical Global Impression of Change (CGIC) measure. METHODS: For assessment of consistency of PEP responses (short-term [ie, sexual event driven] vs 1-month recall), descriptive statistics, correlation coefficients (Pearson and Spearman), and Bland-Altman plots are presented for each time interval. For assessment of convergent validity, descriptive statistics and correlation coefficients (Pearson and Spearman) are presented for each assessment with geometric mean IELT values. Results are also depicted graphically. Geometric mean IELT over the last 4 weeks of treatment and change from baseline (absolute and fold change) were estimated via a general linear model for each category of change in PEP and CGIC, adjusting for baseline IELT. OUTCOMES: PEP items administered via 1-month recall and short-term event-driven responses gave virtually identical results. There was a strong correlation (very good convergent validity) between IELT and responses to PEP and the CGIC. CLINICAL TRANSLATION: Men with lifelong PE can accurately recall their level of sexual functioning over the previous month. The PEP and CGIC are appropriate instruments to measure the subjective response of men with PE to new treatments. STRENGTHS AND LIMITATIONS: Our analyses address gaps in previously published research on PE assessment methodology. Men with acquired PE, men without partners, and men in homosexual relationships were not studied. CONCLUSIONS: In a clinical trial setting, PEP and CGIC are appropriate end points and are likely the optimal combination of PROs for use with IELT to enable a global assessment of patient response to new PE treatments. Althof S, Rosen R, Harty B, et al. Objective and Subjective Measures of Premature Ejaculation: How Closely Do They Correspond and How Well Are the Subjective Measures Recalled? J Sex Med 2020;17:634-644.

The Oxytocin Antagonist Cligosiban Prolongs Intravaginal Ejaculatory Latency and Improves Patient-Reported Outcomes in Men with Lifelong Premature Ejaculation: Results of a Randomized, Double-Blind, Placebo-Controlled Proof-of-Concept Trial (PEPIX).

INTRODUCTION: Cligosiban is an orally administered oxytocin receptor antagonist being developed to treat premature ejaculation (PE). AIM: To determine the safety and efficacy of cligosiban capsules (dose range 400-800 mg) to improve intravaginal ejaculation latency time (IELT) and patient-reported outcomes in men with severe lifelong PE. METHODS: Patients recorded details of at least 4 sexual intercourse events during a 4-week run-in period, after which they underwent baseline assessments. Patients were eligible for the study if they rated their control of ejaculation as poor/very poor and their stopwatch-assessed IELT was ≤1 minute in ≥75% of intercourse attempts. Eligible patients were randomized to an 8-week treatment period with double-blind cligosiban or placebo (to be taken 1 to 6 hours prior to sexual activity). The starting dose was 400 mg (not more than 1 dose per day) which could be increased to 800 mg after 2 and/or 4 weeks of treatment. Assessments were conducted at 2, 4, and 8 weeks. MAIN OUTCOME MEASURE: Efficacy measures were comprised of IELT, self-rating of ejaculation control and ejaculation-related distress (recorded in an electronic diary after each intercourse attempt), premature ejaculation profile, and the Clinical Global Impression of Change. RESULTS: The mean ratio of fold change from baseline in IELT to the last 4 weeks of treatment (cligosiban/placebo) was 1.9 compared to a baseline of 1.0 (P = .0079). The mean increase in IELT from baseline to the last 4 weeks of treatment was 61.0 seconds for cligosiban, which was significantly different from (and 3.6-fold greater than) the mean increase of 16.4 seconds for placebo (P = .0086). Statistically significant improvements in ejaculation control and ejaculation-related personal distress scores were also observed for cligosiban compared to little or no change with placebo. Cligosiban was generally well tolerated, with no serious or severe adverse events or other safety parameters. CLINICAL IMPLICATIONS: This proof-of-concept study demonstrated the potential for cligosiban, an oxytocin antagonist, to successfully treat symptoms of severe lifelong PE. STRENGTHS AND LIMITATIONS: This was a Phase II, randomized, double-blind, placebo-controlled study that was adequately powered to detect a clinically meaningful difference in change in IELT between cligosiban and placebo. Larger studies will be needed to confirm these findings, determine the optimal dose of cligosiban and assess efficacy in men with acquired PE. CONCLUSIONS: Cligosiban was well tolerated, and resulted in significant benefits in both objective and subjective measures of ejaculatory control in men with lifelong PE and therefore offers significant potential as an on-demand, orally administered agent for the treatment of PE. McMahon C, Althof S, Rosen R, et al. The Oxytocin Antagonist Cligosiban Prolongs Intravaginal Ejaculatory Latency and Improves Patient-Reported Outcomes in Men with Lifelong Premature Ejaculation: Results of a Randomized, Double-Blind, Placebo-Controlled Proof-of-Concept Trial (PEPIX). J Sex Med 2019; 16:1178-1187.

The Oxytocin Antagonist Cligosiban Fails to Prolong Intravaginal Ejaculatory Latency in Men with Lifelong Premature Ejaculation: Results of a Randomized, Double-Blind, Placebo-Controlled Phase IIb trial (PEDRIX).

INTRODUCTION: Cligosiban is an orally administered, centrally penetrant oxytocin receptor antagonist being developed to treat premature ejaculation (PE). AIM: To determine the efficacy of 3 dose levels of cligosiban caplets to prolong intravaginal ejaculation latency time (IELT) and improve patient-reported outcomes in men with lifelong PE. METHODS: Patients recorded details of at least 4 sexual intercourse events during a 4-week run-in period, after which they underwent baseline assessments. Patients were eligible for the study if their stopwatch-assessed IELT was ≤1 minute in ≥75% of intercourse attempts and if they met other diagnostic criteria for lifelong PE. Eligible patients (target 220 evaluable) were randomized to double-blind cligosiban 400, 800, or 1200 mg or matching placebo caplets (to be taken 1 to 6 hours prior to sexual activity). Assessments were conducted at 2, 4, and 8 weeks. MAIN OUTCOME MEASURE: Efficacy measures were comprised of IELT, self-rating of ejaculation control and ejaculation-related distress (recorded in an electronic diary after each intercourse attempt), premature ejaculation profile, Patient's Global Impression of Severity, and the Clinical Global Impression of Change. RESULTS: There were no clinically or statistically significant differences between cligosiban (at any dose level) and placebo for the primary endpoint (change in geometric IELT) or any of the secondary endpoints. Cligosiban was well tolerated with a side-effect profile similar to placebo. CLINICAL IMPLICATIONS: This Phase IIb study failed to demonstrate the potential for cligosiban, an oxytocin antagonist, to successfully treat symptoms of severe lifelong PE at doses up to 1200 mg. STRENGTHS AND LIMITATIONS: This was a Phase IIb, randomized, double-blind, placebo-controlled study that was adequately powered but failed to detect a clinically meaningful or statistical difference in change in IELT between cligosiban at 3 dose levels and placebo. This is in contrast to a similarly designed proof-of-concept study where cligosiban was flexibly dosed at doses up to 800 mg and did demonstrate clinically meaningful and statistically significant changes in efficacy parameters. The reasons for this disparity are not known. CONCLUSIONS: Cligosiban was well tolerated but failed to demonstrate efficacy for the treatment of men with lifelong PE at doses up to 1200 mg. Althof S, Osterloh IH, Muirhead GJ, et al. The Oxytocin Antagonist Cligosiban Fails to Prolong Intravaginal Ejaculatory Latency in Men with Lifelong Premature Ejaculation: Results of a Randomized, Double-Blind, Placebo-Controlled Phase IIb trial (PEDRIX). J Sex Med 2019; 16:1188-1198.

Pharmacokinetics, Safety, and Tolerability of Multiple Doses of the Novel Oxytocin Receptor Antagonist Cligosiban in Development for Premature Ejaculation: Two Randomized Clinical Trials in Healthy Subjects.

BACKGROUND: Cligosiban (formerly IX-01) is a selective oxytocin receptor antagonist being developed for the treatment of premature ejaculation (PE). AIM: To investigate the plasma pharmacokinetics, safety, and tolerability of multiple oral doses of cligosiban in healthy male subjects; measure the amount of cligosiban in semen; and evaluate the potential of cligosiban to modulate CYP3A4. METHODS: Both studies were double-blind, placebo-controlled, parallel group designs involving sequential cohorts of 12 subjects each. Cligosiban dosage regimens were 100 mg, 400 mg, 800 mg, 1200 mg, 1,600 mg and 2,400 mg once daily for 10 days, administered as an aqueous dispersion. OUTCOMES: Blood samplings for cligosiban assays and safety assessments were performed throughout both studies. Semen was collected on day 9 at 2-4 hours postdose in study 1 only. Safety assessments included monitoring of adverse events, 12-lead electrocardiography, vital signs, and laboratory safety assessments. Urine samples for assessment of the 6ß-hydroxycortisol/cortisol ratio were collected before dosing on days 1 and 10. RESULTS: Cligosiban was rapidly absorbed after both single and multiple dosing, with maximum plasma concentrations typically measured at 1-3 hours postdose. The terminal half-life was approximately 12 hours, and steady state was achieved by day 3. Exposure increased approximately proportionally to dose after single dosing but less than proportionally after multiple dosing. Accumulation ratios were higher at the lower doses compared with higher doses (2.3 at 100 mg vs 1.1 at 2,400 mg). The mean amount of cligosiban in semen ranged from 0.22 to 2.01 µg over the 100-1,200 mg dose range (<0.0003% of the administered dose). There were no meaningful differences in the urinary 6ß-hydroxycortisol/cortisol ratio after multiple dosing with cligosiban. Cligosiban appeared to be well tolerated at all dose levels. CLINICAL IMPLICATIONS: Cligosiban is well tolerated following once-daily dosing over a wide dose range and does not appear to modulate CYP3A4 activity, suggesting limited potential for perpetrating drug-drug interactions via this mechanism. STRENGTHS & LIMITATIONS: The 2 controlled trials show good toleration and pharmacokinetic data, including negligible amounts of cligosiban in semen at doses expected to be therapeutic. Toleration of cligosiban will need to be confirmed in studies in patients with PE. CONCLUSION: Cligosiban showed a good safety profile at doses predicted to be therapeutic or supratherapeutic along with a pharmacokinetic profile appropriate for as-required or once-daily dosing. There was no evidence that cligosiban inhibited or induced CYP3A4 at doses up to 2,400 mg. Muirhead GJ, Osterloh IH, Whaley S, et al. Pharmacokinetics, Safety, and Tolerability of Multiple Doses of the Novel Oxytocin Receptor Antagonist Cligosiban in Development for Premature Ejaculation: Two Randomized Clinical Trials in Healthy Subjects. J Sex Med 2019;16:213-222.

Pharmacokinetics, Safety, and Tolerability of Single Oral Doses of a Novel Oxytocin Receptor Antagonist-Cligosiban-in Development for Premature Ejaculation: Three Randomized Clinical Trials in Healthy Subjects.

INTRODUCTION: Cligosiban is a selective oxytocin receptor antagonist being developed for the treatment of premature ejaculation (PE). AIM: Three clinical studies investigated the pharmacokinetics (including effect of food and formulation), central penetration, safety, and tolerability of single oral doses of cligosiban in healthy subjects. METHODS: Study 1 was a double-blind, randomized, placebo-controlled, crossover design in 3 cohorts of 10 subjects each. Single doses of 0.3-2,400 mg cligosiban were administered as aqueous solutions or dispersions under fasting and fed (800 mg only) conditions. Studies 2 and 3 were open-label, randomized, crossover designs in 12 subjects each. Study 2 investigated 800 mg cligosiban administered as capsules and aqueous dispersion under fasting conditions, and capsules under fed conditions. Study 3 investigated 1,600 mg cligosiban administered as caplets and aqueous dispersion under fasting conditions, and caplets under fed conditions. MAIN OUTCOME MEASURES: Blood sampling for cligosiban assay and safety assessments were conducted throughout all studies. Cerebrospinal fluid (CSF) samples for cligosiban assay were collected in study 2. RESULTS: Cligosiban was rapidly absorbed under fasting conditions with peak concentrations generally occurring within 1-2 hours post-dose regardless of formulation. Maximum observed plasma concentration (Cmax) and area under the concentration time curve extrapolated to infinity (AUC0-∞) increased approximately dose-proportionally from 0.3-10 mg, but sub-proportionally from 30-2,400 mg. Cligosiban exposure was similar when administered as a dispersion or capsule (800 mg) under fasted conditions, but higher (87% increase) when administered as a caplet compared to the dispersion (1,600 mg). Food decreased the rate of absorption for all 3 formulations (median time to Cmax 3-6 hours compared to 1-2 hours fasted) but increased the extent of absorption (Cmax and AUC0-∞ increased by 75-149% and 33-49%, respectively). Cligosiban was detected in CSF at concentrations approximately 40% of unbound plasma concentrations. Cligosiban was well tolerated at all doses. CLINICAL IMPLICATIONS: Cligosiban is well tolerated over a wide dose range, and has the pharmacokinetic properties to be taken as required prior to sexual intercourse in men with PE and to antagonize the oxytocin receptor in the brain and spinal cord. STRENGTHS & LIMITATIONS: Three controlled trials show similar toleration and pharmacokinetic data. Cligosiban in CSF indicates its likely presence in all central nervous system tissue. These data need to be investigated and confirmed in multiple-dose studies prior to investigation in phase-II studies in men with PE. CONCLUSION: Cligosiban had a good safety/tolerability profile at doses predicted to be therapeutic or supra-therapeutic and a pharmacokinetic profile appropriate for "as-needed" dosing for men with PE. Osterloh IH, Muirhead GJ, Sultana S, et al. Pharmacokinetics, Safety, and Tolerability of Single Oral Doses of a Novel Oxytocin Receptor Antagonist-Cligosiban-in Development for Premature Ejaculation: Three Randomized Clinical Trials in Healthy Subjects. J Sex Med 2018;15:1547-1557.

Assessment of the pharmacokinetics, safety and tolerability of maraviroc, a novel CCR5 antagonist, in healthy volunteers.

AIMS: To evaluate the pharmacokinetics, safety and tolerability of single and multiple oral doses of maraviroc in healthy volunteers. METHODS: Three double-blind, placebo-controlled, dose-escalation studies with either single or multiple doses of maraviroc were conducted in healthy volunteers. Plasma and urine samples were collected to investigate the pharmacokinetics of maraviroc and evaluate any changes with respect to dose and duration/frequency of dosing. Safety and toleration of maraviroc were also assessed. RESULTS: Maraviroc is rapidly absorbed following oral administration, and plasma T(max) is achieved within 0.5-4.0 h postdose. Steady-state plasma concentrations are achieved after 7 consecutive days of dosing. Although the pharmacokinetics of maraviroc is nonproportional over the dose range studied (3-1200 mg), the degree of nonproportionality is small at clinically relevant doses. Renal clearance is approximately 10-12 l h(-1) and appears unaffected by increasing maraviroc doses. Maraviroc does not significantly modulate the activity of CYP2D6 or CYP3A4 at clinically relevant doses. There were no serious adverse events in any of these studies, and doses up to 900 mg were generally well tolerated, with postural hypotension being the dose-limiting event. There was no pattern or dose relationship observed with maraviroc with regard to laboratory abnormalities, including hepatic transaminases. No clinically significant increases in QTc were noted at clinically relevant doses. CONCLUSIONS: Maraviroc is absorbed into the systemic circulation and reaches steady state by day 7 of multiple dosing. It does not significantly influence the activity of major drug-metabolizing enzymes and is well tolerated at clinically relevant doses, with most adverse events being mild or moderate.

Effect of maraviroc on the pharmacokinetics of midazolam, lamivudine/zidovudine, and ethinyloestradiol/levonorgestrel in healthy volunteers.

AIMS: To assess the effect of maraviroc on the pharmacokinetics of midazolam, a sensitive probe CYP3A4 substrate; lamivudine/zidovudine, a combination of nucleoside reverse transcriptase inhibitors (NRTIs); and ethinyloestradiol/levonorgestrel, a combination oral contraceptive. METHODS: Three randomized, double-blind, placebo-controlled studies were conducted in healthy subjects to assess the effect of maraviroc on pharmacokinetics of other drugs. Two, two-period crossover studies were conducted to assess (i) the effect of steady-state maraviroc (300 mg b.i.d.) on pharmacokinetics of midazolam; and (ii) the effect of steady-state maraviroc (300 mg b.i.d.) on the pharmacokinetics of lamivudine/zidovudine. A third two-way crossover study was conducted to evaluate the effect of steady-state maraviroc (100 mg b.i.d.) on the pharmacokinetics of 30 microg ethinyloestradiol/150 microg levonorgestrel (Microgynon). RESULTS: The geometric mean ratios for C(max) and AUC for each of the compounds tested in the presence and absence of maraviroc were between 92% and 121%. There were no notable differences in T(max), t(1/2) or CL(R) (where measured) for any of the compounds. CONCLUSIONS: Maraviroc had no clinically relevant effects on the pharmacokinetics of the CYP3A4 substrate midazolam, the NRTIs zidovudine/lamivudine, or the oral contraceptive steroids ethinyloestradiol and levonorgestrel.

Effects of CYP3A4 inhibitors on the pharmacokinetics of maraviroc in healthy volunteers.

AIMS: To evaluate the influence of cytochrome P450 (CYP) 3A4 inhibitors on the clinical pharmacokinetics of maraviroc, a novel CCR5 antagonist. METHODS: Four open-label, randomized, placebo-controlled studies were conducted in healthy subjects to assess the effect of separate and distinct combinations of CYP3A4 inhibitors on the steady-state pharmacokinetics of maraviroc. Study 1 was a two-way crossover study investigating the influence of saquinavir (SQV; 1200 mg t.i.d.) and ketoconazole (400 mg q.d.) on the pharmacokinetics of maraviroc (100 mg b.i.d.). All subjects received maraviroc for 7 days in both study periods. Cohort 1 subjects also received SQV or placebo and cohort 2 subjects also received ketoconazole or placebo. Study 2 was a parallel-group study including four treatment groups investigating the effects of ritonavir-boosted lopinavir (LPV/r; 400 mg/100 mg b.i.d.), ritonavir-boosted saquinavir (SQV/r; 1000 mg/100 mg b.i.d.), and low-dose ritonavir (RTV; 100 mg b.i.d.) on the steady-state pharmacokinetics of maraviroc (100 mg b.i.d.), and exploring whether maraviroc dose adjustment can compensate for interaction effects. Treatment lasted 28 days and comprised three distinct phases: (i) maraviroc alone on days 1-7; (ii) maraviroc + interactant on days 8-21; and (iii) maraviroc (adjusted dose) + interactant on days 22-28. Study 3 was a two-way crossover study investigating the effects of atazanavir (ATZ; 400 mg q.d.) and ritonavir-boosted atazanavir (ATZ/r; 300 mg/100 mg b.i.d.) on the pharmacokinetics of maraviroc (300 mg b.i.d.). All subjects received maraviroc on days 1-14 of both study periods. Subjects also received ATZ on days 1-7 and ATZ/r on days 8-14 of one treatment period, and placebo on days 1-14 of the other treatment period. Study 4 was a two-way crossover study investigating the effects of ritonavir-boosted tipranavir (TPV/r; 500 mg/200 mg b.i.d.) on the pharmacokinetics of maraviroc (150 mg b.i.d.). Subjects received maraviroc plus TPV/r or placebo on days 1-8. RESULTS: All of the drugs/drug combinations tested (except for TPV/r) increased maraviroc exposure, albeit to different degrees of magnitude. SQV/r caused the largest increase in maraviroc exposure (8.3-fold increase in AUC(tau)), whereas RTV caused the smallest increase in maraviroc exposure (2.6-fold increase in AUC(tau)). Downward adjustment of the maraviroc dose in study 2 during co-administration of HIV protease inhibitors was able to compensate for the interactions. TPV/r had no clinically relevant effect on maraviroc exposure at steady state. There were no treatment-related serious adverse events or discontinuations due to adverse events in any of the studies, and most adverse events were mild or moderate in severity and resolved without intervention. CONCLUSIONS: Potent CYP3A4 inhibitors, including ketoconazole and protease inhibitors (except TPV/r), increase maraviroc exposure. Downward adjustment of the maraviroc dose during co-administration with protease inhibitors can compensate for the interaction. TPV/r does not affect the steady-state pharmacokinetics of maraviroc, and hence no dose adjustment would be warranted.

Effects of CYP3A4 inducers with and without CYP3A4 inhibitors on the pharmacokinetics of maraviroc in healthy volunteers.

AIMS: To assess the potential of known CYP3A4 inducers, with and without CYP3A4 inhibitors, to alter the pharmacokinetic profile of maraviroc. METHODS: Two separate, open, randomized, placebo-controlled studies were conducted in healthy subjects. Study 1 was a 28-day parallel-group study with three treatment groups of 12 subjects each. On days 1-7, all subjects received maraviroc 100 mg b.i.d.; on days 8-21, subjects received maraviroc 100 mg b.i.d. plus either rifampicin 600 mg q.d., efavirenz (EFV) 600 mg q.d., or placebo q.d. as assigned; on days 22-28, the maraviroc dose was increased to 200 mg b.i.d. for patients receiving either rifampicin or EFV. Study 2 was a 21-day, two-way crossover study with three cohorts (12 subjects per cohort). On days 1-21, subjects received maraviroc 300 mg b.i.d. and boosted lopinavir (LPV/r, lopinavir 400 mg + ritonavir 100 mg) or placebo b.i.d. in cohort 1, maraviroc 100 mg b.i.d. and boosted saquinavir (SQV/r, saquinavir 1000 mg + ritonavir 100 mg) or placebo b.i.d. in cohort 2, and maraviroc 100 mg b.i.d. and 1000 mg saquinavir + LPV/r (400 mg/100 mg) or placebo b.i.d. in cohort 3. On days 8-21, subjects in all three cohorts also received EFV 600 mg or placebo q.d. RESULTS: Maraviroc (100 mg b.i.d.) exposure (AUC(12) and C(max)) was reduced in the presence of rifampicin and EFV by approximately 70% and 50%, respectively. Maraviroc AUC(12) and C(max) approached preinduction values when the maraviroc dose was increased to 200 mg b.i.d. for both the rifampicin-treated and EFV-treated groups. Co-administration of LPV/r with maraviroc (300 mg b.i.d.) resulted in geometric mean ratios (GMRs) of 395% and 197% for maraviroc AUC(12) and C(max), respectively, compared with placebo; addition of EFV resulted in GMRs of 253% and 125% for AUC(12) and C(max), respectively. Co-administration of SQV/r with maraviroc (100 mg b.i.d.) resulted in GMRs of 977% and 478% for maraviroc AUC(12) and C(max), respectively, compared with placebo; addition of EFV resulted in GMRs of 500% and 226% for AUC(12) and C(max), respectively. No pharmacokinetic data are reported for cohort 3 because all subjects were discontinued during period 1 due to poor toleration of the drug regimen. There were no serious adverse events reported in either study, and most adverse events were mild or moderate in severity and resolved without intervention. CONCLUSION: As expected with a CYP3A4 substrate, maraviroc exposure (C(max) and AUC(12)) was significantly reduced by the known CYP3A4 inducers, rifampicin and EFV, by approximately 70% and 50%, respectively. Upward adjustment of the maraviroc dose during co-administration with rifampicin or EFV appears to compensate for this reduction. Protease inhibitors (PIs) significantly increased maraviroc exposure; however, the addition of EFV to the maraviroc + PI regimens reduced the magnitude of PI-mediated increase in maraviroc exposure (by approximately 50%), but the net effect was still CYP3A4 inhibition.

The effects of cotrimoxazole or tenofovir co-administration on the pharmacokinetics of maraviroc in healthy volunteers.

AIMS: To assess the potential of cotrimoxazole and tenofovir, drugs which are inhibitors and/or substrates of renal transporters, to alter the pharmacokinetic profile of maraviroc. METHODS: Two randomized, placebo-controlled, two-way crossover studies were conducted in healthy male and female subjects. In study 1, 16 subjects, aged 18-45 years, received maraviroc (300 mg b.i.d.) with and without cotrimoxazole (960 mg b.i.d.; 160 mg trimethoprim and 800 mg sulfamethoxazole). In study 2, 12 subjects, aged 21-45 years, received maraviroc (300 mg b.i.d.) with and without tenofovir (300 mg q.d.). For study 1, blood was collected predose and on days 1-7. In study 2, blood was collected predose, on day 1 and days 3-7. In both studies, blood was collected at intervals up to 12 h postdose on day 7. Urine was collected on day 7, 0-12 h post morning dose. Blood and urine were analysed for maraviroc using liquid chromatography/tandem mass spectrometry. RESULTS: The geometric mean ratios for C(max) and AUC(12) were 119% and 111%, respectively, for maraviroc plus cotrimoxazole and 104% and 103%, respectively, for maraviroc plus tenofovir, compared with maraviroc plus placebo. Renal clearance of maraviroc plus placebo was 8.3 l h(-1) and 8.5 l h(-1) and was 7.8 l h(-1) for maraviroc plus cotrimoxazole and maraviroc plus tenofovir. There were no serious or severe adverse events or any clinically significant changes in laboratory tests, blood pressure, or electrocardiograms. CONCLUSIONS: Neither cotrimoxazole nor tenofovir caused a clinically significant effect on the pharmacokinetics of maraviroc. Maraviroc 300 mg b.i.d. was well tolerated when co-administered with either cotrimoxazole or tenofovir.

A novel probe drug interaction study to investigate the effect of selected antiretroviral combinations on the pharmacokinetics of a single oral dose of maraviroc in HIV-positive subjects.

AIMS: Maraviroc (UK-427 857), an antagonist of the CCR5 receptor with potent anti-HIV activity, was recently approved for use in treatment-experienced patients infected with CCR5-tropic HIV-1. The aim of this study was to evaluate the effect of selected commonly used antiretroviral therapy (ART) combinations on the pharmacokinetics of a single oral dose of maraviroc 300 mg in HIV-positive subjects compared with historical controls. METHODS: In this study, four cohorts of HIV-positive patients (n = 8 each) receiving one of the following combination therapies were recruited: cohort 1--efavirenz + Combivir (lamivudine/zidovudine); cohort 2--efavirenz + didanosine + tenofovir; cohort 3--nevirapine + lamivudine + tenofovir; cohort 4--Kaletra (lopinavir/ritonavir) + stavudine + lamivudine. Subjects continued on their prescribed ART and also received a single oral dose of maraviroc 300 mg. Serial blood samples and urine for determination of maraviroc pharmacokinetics were collected over 12 h postdose. Plasma pharmacokinetic parameters from this study were compared with historical data generated in HIV-positive subjects receiving maraviroc monotherapy in a Phase IIa study. RESULTS: A total of 29 subjects were recruited (eight each in cohorts 1-3, and five in cohort 4). The geometric mean ratios for AUC(12) and C(max) for each treatment group compared with maraviroc monotherapy were: 47% and 67% (cohort 1); 48% and 76% (cohort 2); 101% and 154% (cohort 3); and 265% and 180% (cohort 4), respectively. T(max) was similar in all treatment groups. Mean values for renal clearance ranged from 8.2 l h(-1) (cohort 1) to 13.2 l h(-1) (cohort 4). There were no renal clearance data collected in the comparator study. CONCLUSIONS: The results of this study support those previously seen in healthy volunteer studies that showed that efavirenz reduces maraviroc exposure, whereas lopinavir/ritonavir increases maraviroc exposure. These data also suggest that nevirapine does not lead to a clinically significant effect on maraviroc pharmacokinetics.

Man versus machine: is there an optimal method for QT measurements in thorough QT studies?

Electrocardiographic (ECG) recordings from 3 placebo-controlled thorough QT healthy volunteer studies were used to compare QT intervals obtained by manual measurement with those generated by ECG machines. The effect of the positive control was compared to placebo at each time point for data obtained from both sources. Both manual and automated techniques consistently demonstrated statistically significant prolongation of QTcF with the positive controls. The proportion of outlier values was small for both methods. The pairwise comparison between manual and automated uncorrected QT intervals demonstrated clear differences, with intervals derived from one machine on average 16 to 19 milliseconds shorter and from the other 7 milliseconds longer than the manually measured QT intervals, but these differences disappeared when analyzing QT change from baseline. Both manual and automated, commercially available QT algorithms demonstrated small statistically significant effects on the QTc interval induced by positive controls.

Species differences in the disposition of the CCR5 antagonist, UK-427,857, a new potential treatment for HIV.

UK-427,857 (4, 4-difluoro-N-[(1S)-3-[exo-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl]cyclohexanecarboxamide) is a novel CCR5 antagonist undergoing investigation for use in the treatment of human immunodeficiency virus (HIV) infection. Pharmacokinetic and metabolism studies have been performed in mouse, rat, dog, and human after single and multiple administration by oral and intravenous routes. The compound has physicochemical properties that are borderline for good pharmacokinetics, being moderately lipophilic (log D(7.4) 2.1) and basic (pK(a) 7.3), possessing a number of H-bonding functionalities, and with a molecular weight of 514. The compound was incompletely absorbed in rat (approximately 20-30%) but well absorbed in dog (>70%). Based on in vitro studies in Caco-2 cells, UK-427,857 has relatively poor membrane permeability, and transcellular flux is enhanced in the presence of inhibitors of P-glycoprotein. Further evidence for the involvement of P-glycoprotein in restricting the oral absorption of UK-427,857 was obtained in P-glycoprotein null mice (mdr1a/mdr1b knockout). In these animals, AUC after oral administration was 3-fold higher than in control animals. In oral dose escalation studies in humans, the compound demonstrated nonlinear pharmacokinetics, with increased dose-normalized exposure with increased dose size, consistent with saturation of P-glycoprotein. The oral dose-exposure relationship of UK-427,857 in humans was not reflected in either rat or dog. In animal species and humans, UK-427,857 undergoes some metabolism, with parent compound the major component present in the systemic circulation and excreta. Elimination of radioactive dose was primarily via the feces. In rat, parent compound was secreted via bile and directly into the gastrointestinal tract. Metabolites were products of oxidative metabolism and showed a high degree of structural consistency across species.

The pharmacokinetics and hemodynamics of sildenafil citrate in male hemodialysis patients.

BACKGROUND: Erectile dysfunction (ED) is highly prevalent in men with renal disease. The clearance of sildenafil citrate, a highly effective oral treatment for ED, is decreased in men with severe renal insufficiency, but the pharmacokinetic and hemodynamic profiles during maintenance hemodialysis in men with end-stage renal disease have not been studied. METHODS: Fifteen men undergoing chronic outpatient maintenance hemodialysis received a single 50-mg oral dose of sildenafil on 2 occasions, once 2 hours before, and once 2 hours after hemodialysis, with randomized assignment to sequence. Blood and dialysate samples were collected, and hemodynamic measurements were made. RESULTS: Hemodialysis did not significantly clear either sildenafil or its primary metabolite, UK-103,320. Administration after hemodialysis was associated with a 17% higher peak plasma concentration and earlier time to peak, which were not clinically meaningful, whereas the overall extent of absorption and the elimination half-life were not affected. The average extent of drug bound to plasma protein was approximately 96% in hemodialysis patients. Intradialytic hypotension was not observed more frequently when sildenafil was administered before hemodialysis. Systolic blood pressure tended to decrease less during hemodialysis when subjects were treated with sildenafil before dialysis. CONCLUSION: The present study demonstrates that sildenafil is not cleared by hemodialysis, and the pharmacokinetic profile resembles more closely that observed in normal volunteers than that observed in patients with severe renal insufficiency. In addition, we found that sildenafil does not promote intradialytic hypotension.

The Karolinska cocktail for phenotyping of five human cytochrome P450 enzymes.

OBJECTIVES: Our objectives were (1) to determine whether the drugs caffeine, losartan, omeprazole, debrisoquin (INN, debrisoquine), and quinine can be given simultaneously in low doses as a cocktail for the phenotyping of cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, and 3A4, respectively, and (2) to design an administration schedule to give as few sampling occasions as possible. METHODS: Twenty-four subjects were given oral doses of 100 mg caffeine, 25 mg losartan, 20 mg omeprazole, 10 mg debrisoquin, and 250 mg quinine on separate days. After a washout period of at least 4 days, all drugs were given simultaneously except for quinine, which was given 8 hours after the other drugs. Blood and urine samples were collected to determine parent drug and metabolite concentrations for assessment of phenotyping indices. Any difference between both single and cocktail doses was tested on a log-normal distribution. RESULTS: The phenotypic indices of CYP1A2 (paraxanthine/caffeine in 4-hour plasma), CYP2C9 (losartan/E-3174 [metabolite of losartan] in 0- to 8-hour urine), CYP2C19 (omeprazole/5-hydroxyomeprazole in 3-hour plasma), and CYP3A4 (quinine/3-hydroxyquinine in 16-hour plasma) were not significantly changed when probe drugs were administered alone compared with together, although a tendency toward higher concentrations of losartan was seen during simultaneous administration (95% confidence interval, 0.51-1.002; P =.051). The CYP2D6 phenotypic index (debrisoquin/4-hydroxydebrisoquin in 0- to 8-hour urine) was significantly changed when drugs were given together (95% confidence interval, 0.45-0.87; P =.007), indicating an inhibition of the debrisoquin metabolism. The within-subject coefficients of variation (8%-25%) were much lower than the between-subject coefficients of variation (34%-79%). CONCLUSIONS: The administration of drugs together suggests an inhibition of debrisoquin metabolism caused by the concurrent drugs given. By separating debrisoquin from the other cocktail drugs, this method is likely to be used as a tool to phenotype the enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 with only 2 urinary collections and 2 blood-sampling occasions.

Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality.

AIMS: To determine the absolute bioavailability, dose proportionality and the effects of food on the pharmacokinetics of single oral doses of sildenafil citrate. METHODS: Three open-label, randomized crossover studies were conducted in healthy male subjects. Absolute bioavailability was determined by comparing pharmacokinetic data after administration of single oral and intravenous 50-mg doses of sildenafil (n=12 subjects). Food effects were examined by comparing pharmacokinetic data for sildenafil and its primary circulating metabolite, UK-103,320, after administration of a single oral 100-mg dose in the fasted and fed states (n=34 subjects). Dose proportionality was assessed from pharmacokinetic data obtained after administration of four single oral doses of sildenafil (25, 50, 100 and 200 mg) to 32 subjects. The safety and tolerability of sildenafil were also assessed in all of these studies. RESULTS: The calculated absolute oral bioavailability of sildenafil was 41% (90% CI: 36--47). Food slowed the rate of absorption, delaying mean tmax by approximately 1 h and reducing Cmax by 29% (90% CI: 19--38). Systemic exposure, as assessed by the mean area under the plasma concentration--time curve (AUC), was reduced by 11% (90% CI: 6--16). These food effects were not considered to be of clinical significance. There was statistical evidence of nonproportionality in Cmax and AUC over the dose range 25--200 mg. However the degree of nonproportionality was small, with predicted increases in Cmax and AUC of 2.2- and 2.1-fold, respectively, for a doubling in dose, and was thought to be clinically nonsignificant. Sildenafil was well tolerated in the three studies; the majority of adverse events were mild and transient. CONCLUSIONS: Sildenafil had a mean absolute bioavailability of 41%. Food caused small reductions in the rate and extent of systemic exposure; these reductions are unlikely to be of clinical significance. Across the dose range of 25--200 mg, systemic exposure increased in a slightly greater than dose-proportional manner.

Comparative human pharmacokinetics and metabolism of single-dose oral and intravenous sildenafil.

AIMS: To characterize the absorption, metabolism and excretion of an oral and intravenous (IV) dose of radiolabelled [14C]-sildenafil citrate in healthy male subjects. Specific objectives were to measure the cumulative amount of drug-related radiolabelled material excreted in the urine and faeces to characterize urinary and faecal radioactivity as unchanged sildenafil or its metabolites, and to quantify blood and plasma total radioactivity and unchanged drug concentrations. METHODS: Six healthy male subjects between the ages of 45 and 58 years were enrolled in an open-label, parallel-group study; three subjects received the oral dose and three received the IV dose. Oral drug was administered as a single dose of 50-mg [14C]-sildenafil, and IV drug was administered as a single dose of 25-mg [14C]-sildenafil infused over 25 min. Each dosage form contained 50 microCi of radioactivity. For radioactivity assays, whole blood, plasma, urine and faeces samples were taken predose and at specified intervals up to 5 days postdose. Plasma samples were assayed for sildenafil and the metabolites UK-103,320 and UK-150,564. Metabolite profiling was also performed in plasma, faeces and urine. RESULTS: Absorption of sildenafil after oral administration was rapid and approximately 92% whilst the absolute bioavailability was limited to 38%, due to first-pass metabolism. Mean AUCt values showed that sildenafil accounted for about 60% of the total circulating radioactivity in the plasma after IV administration and for 32% after oral administration. Concentrations of radioactivity in whole blood were lower than in plasma, indicating limited penetration of sildenafil into blood cells. No unchanged sildenafil was detected in either urine or faeces, demonstrating that metabolism was the major mechanism of drug clearance. The principal routes of metabolism were N-demethylation, oxidation and aliphatic dehydroxylation. Sildenafil was well tolerated, with treatment-related adverse events reported by three subjects. Two of these were mild, and there was one case of moderate leg pain. CONCLUSIONS: The pharmacokinetics of radiolabelled [14C]-sildenafil were consistent with rapid absorption, first-pass metabolism and primarily faecal elimination of N-demethylated metabolites.

The effects of age and renal and hepatic impairment on the pharmacokinetics of sildenafil.

AIMS: To investigate the effects of age and renal and hepatic impairment on the pharmacokinetics, tolerability and safety of sildenafil (single 50-mg oral dose) and its major circulating N-desmethyl metabolite, UK-103,320. METHODS: Three open-label, parallel-group studies were conducted. The first study compared sildenafil pharmacokinetics, safety and toleration in 15 healthy young male subjects (mean age 30 years; range 19--45 years) to 15 healthy elderly male subjects (mean age 70 years; range 65--81 years). The second study included eight male volunteers with normal renal function and 16 male volunteers with varying degrees of renal impairment as assessed by measurement of creatinine clearance (CLcr). The third study included 12 male volunteers with normal hepatic function and 12 male volunteers with chronic stable hepatic cirrhosis (Child-Pugh A and B). For all three studies, blood and urine samples were collected predose and at specified intervals up to 48 h postdose for assays of sildenafil and UK-103,320, and measurements of protein binding. RESULTS: Significant differences in Cmax and AUC were observed between the young and the elderly subjects for both the parent drug and the metabolite. In the elderly, AUC values were approximately twice as high and Cmax values 60--70% higher than those for young men, while t1/2 values were approximately 1 h longer for sildenafil and 2 h longer for UK-103,320. Due to a significantly smaller unbound fraction of drug in the elderly, free drug concentrations were only approximately 40% higher in the elderly group compared to the young group. In the renal impairment study, significant correlations with CLcr were demonstrated for sildenafil oral clearance (CL/F) and Cmax and UK-103,320 Cmax and AUC. Pairwise comparisons between subjects with normal renal function and those with severe renal impairment (CLcr<30 ml min-1) supported these findings, showing significant increases in Cmax and AUC for both the parent drug and the metabolite in the severely impaired subjects. The hepatic impairment study demonstrated that the pharmacokinetics of sildenafil were altered in subjects with chronic stable cirrhosis, as shown by a 46% reduction in CL/F and a 47% increase in Cmax compared with subjects with normal hepatic function, suggesting a reduction in first-pass metabolism as well as systemic clearance. The increase in systemic exposure for UK-103,320 was approximately twice that seen for the parent drug. In all three studies, sildenafil was well tolerated, most adverse events were mild and no subjects discontinued treatment. CONCLUSIONS: Sildenafil pharmacokinetics were affected by age and by renal and hepatic impairment, suggesting that a lower starting dose of 25 mg should be considered for patients with severely compromised renal or hepatic function.

The effects of steady-state erythromycin and azithromycin on the pharmacokinetics of sildenafil in healthy volunteers.

AIMS: Sildenafil, an effective oral treatment for erectile dysfunction, is predominantly metabolized by the cytochrome P450 isozyme 3A4, which is inhibited by a number of the macrolide antibiotics. Therefore, two placebo-controlled, parallel-group studies were conducted to evaluate the effects of multiple doses of erythromycin and azithromycin on the pharmacokinetics, safety and tolerability of a single oral 100-mg dose of sildenafil. METHODS: In the erythromycin interaction study, 26 male volunteers (18--45 years of age) received open-label sildenafil 100 mg on day 1. Half received blinded erythromycin (500 mg) twice daily on days 2--6, and the other half received placebo. On day 6, all subjects received a second 100-mg dose of sildenafil. In the azithromycin interaction study, 24 male volunteers (19--33 years of age) received open-label 100 mg sildenafil on day 1. Half then received blinded azithromycin (500 mg) once daily on days 2--4, and the other half received placebo. On day 4, all subjects received another 100-mg dose of sildenafil. In both studies, blood samples were collected on the first and last study day for the analysis of plasma concentrations of sildenafil and its primary metabolite, UK-103,320. RESULTS: Repeated dosing with erythromycin caused statistically significant increases in the AUC and Cmax of sildenafil (2.8-fold and 2.6-fold, respectively) but had no effect on Tmax, kel or t1/2. A statistically significant 1.4-fold increase in the AUC of UK-103,320 was also observed, as well as a significant decrease in kel, resulting in an increase of about 1 h in t1/2. In contrast, repeated dosing with azithromycin caused no significant change in any pharmacokinetic parameter of either sildenafil or UK-103,320. Erythromycin, azithromycin and sildenafil were well tolerated; adverse events were mild and transient. No subject withdrew from either trial for any reason related to study drug. CONCLUSIONS: These results indicate that erythromycin modifies the pharmacokinetics of sildenafil by inhibiting its CYP3A4-mediated first-pass metabolism. Given these data, a lower starting dose of sildenafil (25 mg) may be considered for patients receiving erythromycin or other potent CYP3A4 inhibitors. Azithromycin did not affect the pharmacokinetics of sildenafil; therefore, no adjustment in dosage is necessary for patients receiving these drugs concomitantly.