Mechanistic Model Describing the Time Course of Humoral Immunity Following Ad26.COV2.S Vaccination in Non-Human Primates.

Mechanistic modeling can be used to describe the time course of vaccine-induced humoral immunity and to identify key biologic drivers in antibody production. We used a six-compartment mechanistic model to describe a 20-week time course of humoral immune responses in 56 non-human primates (NHPs) elicited by vaccination with Ad26.COV2.S according to either a single-dose regimen (1 × 1011 or 5 × 1010 viral particles [vp]) or a two-dose homologous regimen (5 × 1010 vp) given in an interval of 4 or 8 weeks. Humoral immune responses were quantified by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike-specific binding antibody concentrations as determined by spike protein-enzyme-linked immunosorbent assay. The mechanistic model adequately described the central tendency and variability of binding antibody concentrations through 20 weeks in all vaccination arms. The estimation of mechanistic modeling parameters revealed greater contribution of the antibody production mediated by short-lived cells as compared with long-lived cells in driving the peak response, especially post second dose when a more rapid peak response was observed. The antibody production mediated by long-lived cells was identified as relevant for generating the first peak and for contributing to the long-term time course of sustained antibody concentrations in all vaccination arms. The findings contribute evidence on the key biologic components responsible for the observed time course of vaccine-induced humoral immunity in NHPs and constitute a step toward defining immune biomarkers of protection against SARS-CoV-2 that might translate across species. SIGNIFICANCE STATEMENT: We demonstrate the adequacy of a mechanistic modeling approach describing the time course of binding antibody concentrations in non-human primates (NHPs) elicited by different dose levels and regimens of Ad26.COV2.S. The findings are relevant for informing the mechanism-based accounts of vaccine-induced humoral immunity in NHPs and translational research efforts aimed at identifying immune biomarkers of protection against SARS-CoV-2 infection.

Safety, Tolerability, and Pharmacokinetics of JNJ-1802, a Pan-serotype Dengue Direct Antiviral Small Molecule, in a Phase 1, Double-Blind, Randomized, Dose-Escalation Study in Healthy Volunteers.

BACKGROUND: Dengue is a growing global health threat with no specific antiviral drugs available for treatment or prophylaxis. This first-in-human, double-blind, randomized, placebo-controlled study aimed to examine the safety, tolerability, and pharmacokinetics of increasing single and multiple oral doses of JNJ-1802, a pan-serotype dengue antiviral small molecule. METHODS: Eligible healthy participants (18-55 years of age) were randomized to receive oral JNJ-1802 in fasted conditions as (1) single doses (50-1200 mg; n = 29) or placebo (n = 10); or (2) once-daily doses (50-560 mg for 10 consecutive days or 400 mg for 31 days; n = 38) or placebo (n = 9). Safety and tolerability were evaluated throughout the study. Plasma and urine samples were collected at predetermined time points to characterize pharmacokinetics. RESULTS: JNJ-1802 was generally safe and well-tolerated. One grade 3 adverse event (depression) was reported but not considered drug-related by the investigator. Two grade 2 events of rash occurred (multiple-dose part) that were considered very likely related to JNJ-1802 by the investigator and resolved. No clinically relevant changes were observed in laboratory tests, electrocardiograms, or vital signs.JNJ-1802 exposure after single or multiple doses increased dose-proportionally from 50 to 150 mg and less than dose-proportionally for higher doses. The terminal elimination half-life was 6.3-9.2 days and the accumulation factor was 4.3-7.3 after 10 days and 14.6 after 31 days with low amounts of unchanged drug in urine (<0.001% of the 400 mg dose). CONCLUSIONS: Pharmacokinetics and safety results of JNJ-1802 support further clinical development for the treatment and prevention of dengue infection.

Quantifying Antibody Persistence After a Single Dose of COVID-19 Vaccine Ad26.COV2.S in Humans Using a Mechanistic Modeling and Simulation Approach.

Understanding persistence of humoral immune responses elicited by vaccination against coronavirus disease 2019 (COVID-19) is critical for informing the duration of protection and appropriate booster timing. We developed a mechanistic model to characterize the time course of humoral immune responses in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-seronegative adults after primary vaccination with the Janssen COVID-19 vaccine, Ad26.COV2.S. The persistence of antibody responses was quantified through mechanistic modeling-based simulations. Two biomarkers of humoral immune responses were examined: SARS-CoV-2 neutralizing antibodies determined by wild-type virus neutralization assay (wtVNA) and spike protein-binding antibodies determined by indirect spike protein enzyme-linked immunosorbent assay (S-ELISA). The persistence of antibody responses was defined as the period of time during which wtVNA and S-ELISA titers remained above the lower limit of quantification. A total of 442 wtVNA and 1,185 S-ELISA titers from 82 and 220 participants, respectively, were analyzed following administration of a single dose of Ad26.COV2.S (5 × 1010 viral particles). The mechanistic model adequately described the time course of observed wtVNA and S-ELISA serum titers and its associated variability up to 8 months following vaccination. Mechanistic model-based simulations show that single-dose Ad26.COV2.S elicits durable but waning antibody responses up to 24 months following immunization. Of the estimated model parameters, the production rate of memory B cells was decreased in older adults relative to younger adults, and the antibody production rate mediated by long-lived plasma cells was increased in women relative to men. A steeper waning of antibody responses was predicted in men and in older adults.

Zidovudine and lamivudine reach higher concentrations in ventricular than in lumbar human cerebrospinal fluid.

OBJECTIVE: For the treatment of HIV-1-related brain disease and for the prevention of the brain becoming a viral reservoir, it is important that antiretroviral agents reach sufficient concentrations in the CNS. To date, human brain pharmacokinetic data are solely derived from lumbar cerebrospinal fluid (CSF) and mostly originate from single samples. DESIGN: We determined concentrations of antiretroviral drugs in serial samples of ventricular CSF and compared these to the concentrations in serum and lumbar CSF of these patients. METHODS: Two treatment-naïve HIV-1-infected patients received external ventricular drainage for obstructive hydrocephalus. Starting with a combination antiretroviral regimen (cART), ventricular CSF, and subsequently lumbar CSF, with parallel serum, was frequently collected. Drug concentrations were determined and CSF-to-serum ratios were calculated. RESULTS: High concentrations, resulting in high CSF-to-serum ratios, were found in the ventricular CSF of the three substances zidovudine, lamivudine and indinavir, whereas this was not observed for stavudine, ritonavir, saquinavir and efavirenz. Concentrations of zidovudine and lamivudine were up to four times greater in CSF from the ventricles than in lumbar CSF of the same patient. The zidovudine concentrations in the ventricular CSF exceeded serum concentrations by a factor of 1.4. CONCLUSION: Unexpectedly high concentrations of some antiretrovirals in the ventricular CSF, the site close to the brain parenchyma where HIV is located, should be considered when the cART regimen is aiming at CNS viral replication.

Single- and multiple-dose pharmacokinetics and safety of pimodivir, a novel, non-nucleoside polymerase basic protein 2 subunit inhibitor of the influenza A virus polymerase complex, and interaction with oseltamivir: a Phase 1 open-label study in healthy volunteers.

AIMS: The aim of this study was to evaluate the drug-drug interaction between pimodivir, a novel, non-nucleoside polymerase basic protein 2 (PB2) subunit inhibitor of the influenza A virus polymerase complex, and oseltamivir, to assess the feasibility of this combination therapy. Furthermore, single- and multiple-dose pharmacokinetics and safety of pimodivir in healthy volunteers were assessed. METHODS: In Part 1 of this open-label Phase 1 study, healthy volunteers (n = 18) were randomized to one of six cross-over treatment sequences, each comprising administration of oseltamivir 75 mg or pimodivir 600 mg or combination thereof twice daily on Days 1-4, followed by a single morning dose on Day 5. Between each treatment session, there was a minimum 5-day washout period. In Part 2, healthy volunteers (n = 16) randomly received pimodivir 600 mg or placebo (3:1) twice daily on Days 1-9, followed by a single morning dose on Day 10. Pharmacokinetics of pimodivir, oseltamivir and oseltamivir carboxylate, and safety were assessed. RESULTS: In Part 1, co-administration of pimodivir with oseltamivir increased the Cmax of pimodivir by 31% (90% CI: 0.92-1.85) with no change in Cmin or AUC12h . Pimodivir had no effect on oseltamivir or oseltamivir carboxylate pharmacokinetics. In Part 2, after single- and multiple-dose administration of pimodivir, there was a 1.2- and 1.8-fold increase in Cmax and AUC12h , respectively, between Day 1 and Day 10. The most frequently reported treatment-emergent adverse event was diarrhoea (n = 7 each in Part 1 and 2). CONCLUSION: Combination treatment with pimodivir and oseltamivir in healthy volunteers showed no clinically relevant drug-drug interactions. No safety concerns were identified with pimodivir 600 mg twice daily alone or in combination with oseltamivir 75 mg twice daily.

Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Relationships of Etravirine in HIV-1-Infected, Treatment-Experienced Children and Adolescents in PIANO.

PIANO (NCT00665847) investigated etravirine pharmacokinetics, efficacy, and safety in children and adolescents. Treatment-experienced, HIV-1-infected patients (≥6 to <18 years) received etravirine 5.2 mg/kg twice daily (maximum 200 mg twice daily) plus background antiretrovirals. A population pharmacokinetic model was developed, and etravirine C0h and AUC0-12h were estimated. Relationships among intrinsic/extrinsic factors and etravirine pharmacokinetics and pharmacokinetics with pharmacodynamics were assessed. The best model describing etravirine pharmacokinetics consisted of a single compartment with sequential zero- and first-order absorption following a lag time. Interindividual variability terms were included on clearance (CL/F) and the first-order input rate constant (KA). The final model estimates (coefficient of variation, %) for CL/F and KA were 46.3 (11) L/h and 1.07 (34) h-1 , respectively. Overall, median (range) estimated etravirine C0h and AUC0-12h were 287 (2-2276) ng/mL and 4560 (62-28,865) ng · h/mL, respectively. Exposure was slightly lower in adolescents vs children. Sex and adherence did not affect etravirine pharmacokinetics. Factors significantly affecting etravirine exposure were body weight (higher with lower weight), race (lower in Asians than in white or black patients), and the use of certain HIV protease inhibitors. Virologic response (<50 copies/mL at week 48) was lower in the lowest etravirine AUC0-12h quartile vs the upper 3 quartiles (41% vs 67% to 76%). Rash occurred more frequently in the highest quartile than in the lower 3 quartiles (52% versus 8% to 20%). Etravirine 5.2 mg/kg twice daily in treatment-experienced, HIV-1-infected children and adolescents provides comparable exposure to that in adults receiving etravirine 200 mg twice daily and is the recommended dose for children and adolescents.

Bioavailability and bioequivalence of a darunavir 800-mg tablet formulation compared with the 400-mg tablet formulation.

UNLABELLED: Once-daily darunavir/ritonavir (800/100 mg), plus other antiretrovirals, is recommended for HIV-1-infected patients. Low therapy adherence is linked with poor outcomes. Pill burden can impact adherence. An 800-mg darunavir tablet would reduce pill burden. OBJECTIVES: To assess the relative oral bioavailability (NCT01052883) and bioequivalence (NCT01308658) of a darunavir 800-mg tablet vs. 2 × 400-mg tablets. METHODS: In two phase I, open-label, randomized, crossover, single-center studies, healthy volunteers received once-daily ritonavir (100 mg, days 1 - 5) and a single 800-mg darunavir dose: 2 × 400-mg tablets (reference) or 1 × 800- mg tablet (test) on day 3 and vice versa after a ≥ 7-day wash-out. Each study had fasted (n = 16 (bioavailability); n = 83 (bioequivalence)) and fed panels (n = 16; n = 45, respectively). Pharmacokinetic profiles and tolerability were assessed. RESULTS: No volunteers discontinued for treatment-related reasons. Least-square mean ratios (test vs. reference) for darunavir maximum plasma concentrations (C(max)), area under the concentration-time curve from zero to infinity (AUC(0-∞)) were: 1.06 and 1.15 (bioavailability), and 1.02 and 1.00 (bioequivalence), respectively (fasted); 0.89 and 0.88 (bioavailability), and 0.96 and 0.98 (bioequivalence), respectively (fed). 90% confidence intervals (CI) were within 80.00 - 125.00%, except bioavailability AUC(0-∞) (fed and fasted conditions). Median time to C(max) was comparable for both formulations. No clinically relevant differences in adverse events or laboratory abnormalities occurred between formulations. CONCLUSIONS: Bioequivalence was demonstrated for the 800-mg darunavir tablet (fasted and fed conditions). This formulation can reduce pill burden and potentially increase adherence for HIV-1-infected patients in whom once-daily darunavir/ritonavir 800/100 mg is appropriate.

Bioequivalence of a darunavir/cobicistat fixed-dose combination tablet versus single agents and food effect in healthy volunteers.

BACKGROUND: Darunavir requires pharmacokinetic enhancement to increase its bioavailability. Cobicistat is potentially an alternative pharmacokinetic booster to ritonavir. Bioequivalence of a darunavir/cobicistat fixed-dose combination (FDC) versus darunavir and cobicistat co-administered as single agents and the effect of a high-fat meal on the pharmacokinetics of the FDC were evaluated. METHODS: In this Phase I, open-label, randomized, three-panel, crossover study (NCT01619527), healthy volunteers received a single dose of darunavir (800 mg) with cobicistat (150 mg) as either an FDC or as single agents co-administered under fasted (panel 1, n=74) or fed (breakfast, panel 2, n=40) conditions, or as the FDC under fasted versus fed (high-fat breakfast) conditions (panel 3, n=19), with a ≥7 day washout period between treatments. Pharmacokinetic profiles, safety and tolerability were assessed. RESULTS: 90% confidence intervals of the least square mean ratios for darunavir and cobicistat maximum plasma concentration and area under the plasma concentration-time curve (AUC) were all within 80.00% and 125.00% in panels 1 and 2. Administration of the FDC with a high-fat breakfast significantly increased darunavir maximum plasma concentration 2.27-fold and AUC 1.63-1.70-fold, whereas cobicistat pharmacokinetics were unaffected. No volunteers discontinued due to adverse events (AEs). All AEs were grade 1 or 2. Overall, 27 (20%) and 26 (20%) volunteers had ≥1 AE at least possibly related to darunavir and cobicistat, respectively. CONCLUSIONS: Bioequivalence of the darunavir/cobicistat 800/150-mg FDC was demonstrated versus darunavir and cobicistat co-administered as single agents under fasted or fed conditions. Food increased darunavir exposure, therefore, darunavir/cobicistat should be administered with food.

Pharmacokinetics and pharmacodynamics of boosted once-daily darunavir.

The ability to dose antiretroviral agents once daily simplifies the often complex therapeutic regimens required for the successful treatment of HIV infection. Thus, once-daily dosing can lead to improved patient adherence to medication and, consequently, sustained virological suppression and reduction in the risk of emergence of drug resistance. Several trials have evaluated once-daily darunavir/ritonavir in combination with other antiretrovirals (ARTEMIS and ODIN trials) or as monotherapy (MONET, MONOI and PROTEA trials) in HIV-1-infected adults. Data from ARTEMIS and ODIN demonstrate non-inferiority of once-daily darunavir/ritonavir against a comparator and, together with pharmacokinetic data, have established the suitability of once-daily darunavir/ritonavir for treatment-naive and treatment-experienced patients with no darunavir resistance-associated mutations. The findings of ARTEMIS and ODIN have led to recent updates to treatment guidelines, whereby once-daily darunavir/ritonavir, given with other antiretrovirals, is now a preferred treatment option for antiretroviral-naive adult patients and a simplified treatment option for antiretroviral-experienced adults who have no darunavir resistance-associated mutations. Once-daily dosing with darunavir/ritonavir is an option for treatment-naive and for treatment-experienced paediatric patients with no darunavir resistance-associated mutations based on the findings of the DIONE trial and ARIEL substudy. This article reviews the pharmacokinetics, efficacy, safety and tolerability of once-daily boosted darunavir. The feasibility of darunavir/ritonavir monotherapy as a treatment approach for some patients is also discussed. Finally, data on a fixed-dose combination of 800/150 mg of darunavir/cobicistat once daily are presented, showing comparable darunavir bioavailability to that obtained with 800/100 mg of darunavir/ritonavir once daily.

Pharmacokinetics of darunavir in fixed-dose combination with cobicistat compared with coadministration of darunavir and ritonavir as single agents in healthy volunteers.

This study compared the bioavailability of two candidate fixed-dose combinations (FDCs: G003 and G004) of darunavir/cobicistat 800/150 mg with that of darunavir 800 mg and ritonavir 100 mg coadministered as single agents. Short-term safety and tolerability of the FDC formulations were also assessed. This open-label trial included 36 healthy volunteers and assessed steady-state pharmacokinetics of darunavir over 3 randomized, 10-day treatment sequences, under fed conditions. Blood samples for determination of plasma concentrations of darunavir and cobicistat or ritonavir were taken over 24 hours on day 10 and analyzed by liquid-chromatography tandem mass-spectroscopy. Darunavir AUC24h following administration of the FDCs (G003: 74,780 ng ∙ h/mL and G004: 76,490 ng ∙ h/mL) was comparable to that following darunavir/ritonavir (78,410 ng ∙ h/mL), as was Cmax (6,666 and 6,917 ng/mL versus 6,973 ng/mL, respectively). Modestly lower C0h (1,504 and 1,478 ng/mL versus 2,015 ng/mL) and Cmin (1,167 and 1,224 ng/mL versus 1,540 ng/mL) values were seen with the FDCs. Short-term tolerability of the FDCs was comparable to that of darunavir/ritonavir when administered as single agents. The most common adverse events reported were headache, gastrointestinal upset, or rash. Cobicistat is an effective pharmacoenhancer of darunavir when administered as an FDC. Short-term administration of darunavir/ritonavir or darunavir/cobicistat was generally well tolerated.

The effect of rilpivirine on the pharmacokinetics of methadone in HIV-negative volunteers.

Antiretrovirals may influence methadone exposure in HIV-1-infected patients receiving methadone for opiate addiction. Rilpivirine is a non-nucleoside reverse transcriptase inhibitor for treating HIV-1 infection. In this open-label trial (NCT00744770), 13 HIV-negative volunteers continued on their regular stable methadone therapy (60 to 100 mg once daily; Days -14 to 12), with rilpivirine coadministration (Days 1 to 11). Methadone and rilpivirine pharmacokinetics and opiate withdrawal symptoms (Short Opiate Withdrawal Scale, Desires for Drugs Questionnaire, pupillometry) were evaluated. Rilpivirine decreased methadone minimum and maximum plasma concentrations (Cmin ; Cmax ) and area under the plasma concentration-time curve versus methadone alone (least-square mean ratio; 90% confidence interval) by 22% (0.78; 0.67, 0.91), 14% (0.86; 0.78, 0.95), and 16% (0.84; 0.74, 0.95), respectively (R-methadone), and 21% (0.79; 0.67, 0.92), 13% (0.87; 0.78, 0.97), and 16% (0.84; 0.74, 0.96), respectively (S-methadone). Rilpivirine pharmacokinetics with methadone were consistent with historic data. No clinically relevant opiate withdrawal symptoms were reported. Methadone and rilpivirine coadministration was generally well tolerated. No grade 3/4 adverse events (AEs), serious AEs, or discontinuations due to AEs were seen. No methadone dose adjustment is prompted by rilpivirine coadministration. Clinical monitoring for opiate withdrawal is recommended, as some patients may require adjustment of methadone maintenance therapy.

Antiviral activity, pharmacokinetics, and safety of the HIV-1 protease inhibitor TMC310911, coadministered with ritonavir, in treatment-naive HIV-1-infected patients.

OBJECTIVES: TMC310911 is a novel HIV type-1 (HIV-1) protease inhibitor with broad in vitro antiviral activity. In this phase 2a, open-label randomized study, the antiviral activity, pharmacokinetics, and safety and tolerability of ritonavir-boosted TMC310911 was assessed. METHODS: In this study, treatment-naive HIV-1 patients (aged 18-60 years) received 1 of the 4 dosing regimens of TMC310911: 150 mg twice-daily (bid) (n = 8), 300 mg bid (n = 8), 75 mg bid (n = 9), or 300 mg once-daily (qd) (n = 8), for 14 days, all coadministered with 100 mg of ritonavir, as only antiretroviral therapy. RESULTS: The mean change from baseline in HIV-1 RNA (log10 copies per milliliter; primary efficacy endpoint) was -1.30 (75 mg bid), -1.14 (150 mg bid), -1.07 (300 mg bid), and -1.06 (300 mg qd) on day 8 and -1.53 (75 mg bid), -1.79 (150 mg bid), -1.69 (300 mg bid), and -1.55 (300 mg qd) on day 15. At steady state (day 14), the mean maximum plasma concentration and mean area under the plasma concentration-time curve from 0 to 12 hours tended to increase dose proportionally for bid doses; TMC310911 daily exposures for the 300 mg qd treatment and 150 mg bid treatment were comparable. The most common (≥ 10%) treatment-emergent adverse events were fatigue (27.3%) and nausea (12.1%); no deaths or serious treatment-emergent adverse events were reported in this study. CONCLUSIONS: Combination treatment with TMC310911 and ritonavir showed potent antiviral activity (>1.5 log10 copies/mL decrease in plasma HIV-1 RNA) at all evaluated doses, and treatment was generally safe and well tolerated.

Safety and pharmacokinetics of the HIV-1 protease inhibitor TMC310911 coadministered with ritonavir in healthy participants: results from 2 phase 1 studies.

OBJECTIVES: To evaluate safety, tolerability, and pharmacokinetics of TMC310911, a novel human immunodeficiency virus type-1 protease inhibitor. METHODS: Healthy participants aged 18-55 years with body mass index 18-30 kg/m were enrolled in 2 phase 1 studies. In the first-in-human, single-dose study, 18 participants received placebo or TMC310911 (75-2000 mg) in the double-blind phase and 8 participants received 300 or 600 mg of TMC310911 [administered alone or with 100 mg ritonavir twice daily (bid)] in the subsequent open-label phase. The multiple-dose double-blind study included 5 successive treatment sessions wherein healthy participants received placebo or TMC310911 [300 mg bid, 600 mg once daily or 150 mg bid (plus 100 mg ritonavir bid), 900 mg bid (alone) or 300 mg bid (plus ritonavir 50 mg bid)]; in all sessions, TMC310911 and ritonavir were administered for 6 and 9 days, respectively. RESULTS: In the single-dose study, no dose-limiting toxicity was observed up to 2000 mg of TMC310911. Systemic exposure to TMC310911 generally increased in a dose-proportional manner after the single- or multiple-dose administrations. Coadministration of ritonavir increased the systemic exposure to TMC310911. The mean Cmax and area under plasma concentration-time curve values (single-dose: 1200 mg TMC310911) were higher under fasted conditions than in fed condition. In both studies, most treatment-emergent adverse events were related to gastrointestinal system. CONCLUSIONS: TMC310911 exhibited a linear pharmacokinetic profile after the single- (up to 2000 mg) and multiple-dose (up to 900 mg) administrations; ritonavir improved the pharmacokinetic profile of TMC310911. TMC310911 was generally safe and tolerable when administered with or without ritonavir.

The effect of single- and multiple-dose etravirine on a drug cocktail of representative cytochrome P450 probes and digoxin in healthy subjects.

The effect of etravirine on cytochrome P450 (CYP) enzymes and P-glycoprotein were evaluated in two randomized, crossover trials in healthy subjects. A modified Cooperstown 5 + 1 cocktail was utilized to determine the effects of etravirine on single-dose pharmacokinetics of model CYP probes. The cocktail was administered alone, then, after a 14-day washout, etravirine 200 mg twice daily (bid) was given for 14 days with cocktail on days 1 and 14. In a separate study, digoxin (0.5 mg) was administered alone, then, after a 14-day washout, etravirine 200 mg bid was administered for 12 days with digoxin on day 8. In the cocktail study, the AUClast least squares mean (LSM) ratios (90% confidence intervals [CIs]) for cocktail + etravirine versus cocktail were 0.93 (0.88, 0.99; paraxanthine), 0.58 (0.44, 0.75; 7-OH-S-warfarin), 0.43 (0.20, 0.96; 5-OH-omeprazole), 0.85 (0.78, 0.94; dextrorphan), and 0.69 (0.64, 0.74; midazolam). Digoxin AUC0-8h was slightly increased with etravirine coadministration (LSM ratio 1.18 [0.90, 1.56]). These data suggest that etravirine is a weak CYP3A isozyme inducer and minimally inhibits CYP2C9, 2C19, and P-glycoprotein activity.

Pharmacokinetic evaluation of the interaction between etravirine and rifabutin or clarithromycin in HIV-negative, healthy volunteers: results from two Phase 1 studies.

OBJECTIVES: Drug-drug interactions between etravirine and rifabutin or clarithromycin were examined in two separate open-label, randomized, two-period, crossover trials in HIV-negative, healthy volunteers. METHODS: Rifabutin study: 16 participants received 300 mg of rifabutin once daily (14 days) and then 800 mg of etravirine twice daily (Phase 2 formulation; 21 days) plus 300 mg of rifabutin once daily (days 8-21). Clarithromycin study: 16 participants received 200 mg of etravirine twice daily (commercial formulation; 8 days) and then 500 mg of clarithromycin twice daily (13 days) plus 200 mg of etravirine twice daily (days 6-13). A 14 day washout period between treatments was mandatory in both studies. Full pharmacokinetic profiles of each drug and safety/tolerability were assessed. RESULTS: Rifabutin decreased etravirine exposure by 37%; etravirine decreased rifabutin and 25-O-desacetyl rifabutin exposure by 17%. Clarithromycin increased etravirine exposure by 42%, whereas etravirine decreased clarithromycin exposure by 39% and increased 14-OH clarithromycin exposure by 21%. No serious adverse events were reported in either trial. CONCLUSIONS: Short-term etravirine coadministration with rifabutin or clarithromycin was well tolerated. Etravirine can be coadministered with 300 mg of rifabutin once daily in the absence of an additional potent cytochrome P450 inducer. No dose adjustments are required upon etravirine/clarithromycin coadministration, but alternatives to clarithromycin are recommended when used for Mycobacterium avium complex prophylaxis or treatment.

Pharmacokinetics of darunavir after administration of an oral suspension with low-dose ritonavir and with or without food.

This 2-part, phase 1, open-label, randomized, crossover study (NCT00752310) assessed ritonavir-boosted darunavir bioavailability (oral suspension vs. tablets), and steady-state darunavir pharmacokinetics (suspension). Part 1: 20 healthy adults randomly received 3 treatments with a ≥7-day washout between treatments; twice-daily ritonavir (100 mg, days 1-5) with darunavir (600 mg, day 3) as 2 × 300-mg tablets (fed, reference), or 6 mL of a 100-mg/mL suspension (fed or fasted, test). Part 2: 18 healthy volunteers received twice-daily darunavir (suspension, 600 mg days 1-6, one dose day 7) with twice-daily ritonavir (100 mg, days 1-9). Darunavir pharmacokinetics were evaluated (part 1 day 3; part 2 day 7). Safety/tolerability were assessed. In part 1, 90% confidence intervals for darunavir Cmax and AUC were all within 80-125% for suspension (fed or fasted) versus tablets (fed). Steady-state darunavir (suspension) pharmacokinetics in part 2 were similar to historic controls (tablets). No clinically relevant differences in adverse events or laboratory abnormalities occurred between treatments. Darunavir administered as an oral suspension or tablets (both with low-dose ritonavir) showed comparable bioavailability in healthy adults after a single dose. Steady-state darunavir pharmacokinetics (suspension, 600/100 mg twice daily) were consistent with historic controls; this formulation is considered suitable for pediatric use and for adults who cannot swallow tablets.

Pharmacokinetic interaction between etravirine or rilpivirine and telaprevir in healthy volunteers: A randomized, two-way crossover trial.

Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) may require treatment with an HIV non-nucleoside reverse transcriptase inhibitor (NNRTI), for example, rilpivirine or etravirine, and an HCV direct-acting antiviral drug such as telaprevir. In a two-panel, two-way, crossover study, healthy volunteers were randomized to receive etravirine 200 mg twice daily ± telaprevir 750 mg every 8 hours or rilpivirine 25 mg once daily ± telaprevir 750 mg every 8 hours. Pharmacokinetic assessments were conducted for each drug at steady-state when given alone and when coadministered; statistical analyses were least-square means with 90% confidence intervals. Telaprevir minimum plasma concentration (Cmin), maximum plasma concentration (Cmax), and area under the concentration-time curve (AUC) decreased 25%, 10%, and 16%, respectively, when coadministered with etravirine and 11%, 3%, and 5%, respectively, when coadministered with rilpivirine. Telaprevir did not affect etravirine pharmacokinetics, but increased rilpivirine Cmin, Cmax, and AUC by 93%, 49%, and 78%, respectively. Both combinations were generally well tolerated. The small decrease in telaprevir exposure when coadministered with etravirine is unlikely to be clinically relevant. The interaction between telaprevir and rilpivirine is not likely to be clinically relevant under most circumstances. No dose adjustments are deemed necessary when they are coadministered.

Lack of an effect of rilpivirine on the pharmacokinetics of ethinylestradiol and norethindrone in healthy volunteers.

UNLABELLED: Rilpivirine is a human immunodeficiency virus Type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitor. OBJECTIVE: Rilpivirine metabolism involves cytochrome P450 3A4 (CYP3A4). This trial (ClinicalTrials. gov number: NCT00739622) evaluated the interaction between rilpivirine and ethinylestradiol/norethindrone (combination oral contraceptives), which are metabolized by multiple pathways, including CYP3A4. METHODS: During three consecutive 28-day cycles, 18 HIV-negative females received once-daily ethinylestradiol (35 µg)/norethindrone (1 mg) (Days 1 - 21); Days 22 - 28 were pill-free. Only in Cycle 3 was once-daily rilpivirine (25 mg) co-administered (Days 1 - 15). Minimum and maximum plasma concentrations (Cmin; Cmax) and area under the plasma concentration-time curve over 24 hours (AUC24h) of ethinylestradiol/norethindrone (Day 15, Cycles 2 and 3) and rilpivirine (Day 15, Cycle 3) were evaluated. RESULTS: Rilpivirine coadministration had no effect on (least square mean ratio, 90% confidence interval) ethinylestradiol Cmin (1.09, 1.03 - 1.16) or AUC24h (1.14, 1.10 - 1.19), but increased Cmax by 17% (1.17, 1.06 - 1.30), which is unlikely to affect ethinylestradiol pharmacodynamics. Norethindrone pharmacokinetics were unaffected by rilpivirine (AUC24h: 0.89, 0.84 - 0.94; Cmin: 0.99, 0.90 - 1.08; Cmax: 0.94, 0.83 - 1.06). Steady-state rilpivirine pharmacokinetics with ethinylestradiol/norethindrone was comparable with historical data for rilpivirine alone. Rilpivirine with ethinylestradiol/norethindrone was generally well tolerated. No new safety events were identified. CONCLUSIONS: Co-administration of rilpivirine, at the therapeutic dosing regimen, with ethinylestradiol/norethindrone does not affect hormone pharmacokinetics, and is, therefore, unlikely to affect the efficacy or safety of this oral hormonal contraceptive. Rilpivirine pharmacokinetics was not affected by ethinylestradiol/norethindrone. Rilpivirine (25 mg once daily) can be co-administered with ethinylestradiol/norethindrone-based contraceptives without dose modification.

Single-dose pharmacokinetics of pediatric and adult formulations of etravirine and swallowability of the 200-mg tablet: results from three Phase 1 studies.

OBJECTIVES: Three studies were conducted to assess the pharmacokinetics, methods of administration and ease of swallowability of etravirine tablets. METHODS: Two randomized studies in healthy adults investigated the single-dose pharmacokinetics of etravirine in various dosage strengths and the effects of dispersion in water and film-coating. A third study explored swallowability of etravirine 200-mg tablets in HIV-infected patients. First study: 37 volunteers received 1 × 100-mg non-coated tablet (reference), 4 × 25-mg noncoated tablets and 1 × 100-mg non-coated tablet dispersed in 100 ml water. Second study: 24 volunteers received 2 × 100-mg non-coated tablets (reference), 2 × 100-mg coated tablets, 1 × 200-mg non-coated and 1 × 200-mg coated tablet. Pharmacokinetic parameters were determined using non-compartmental analysis and least square means (LSM) ratios and 90% confidence intervals (CI) were calculated. Third study: 49 virologically-suppressed patients already on an etravirine-containing regimen rated the swallowability of two etravirine formulations (200-mg non-coated and 200-mg coated tablets). RESULTS: In the first study LSM ratios (90% CI) for the etravirine area under the plasma concentration-time curve (AUC) administered either as 4 × 25-mg tablets or 100-mg tablet dispersed were: 0.91 (0.85 to 0.98) and 0.97 (0.90 to 1.03), respectively. In the second study, when comparing a 200-mg non-coated and coated tablet to 2 × 100-mg non-coated tablets, LSM ratios for etravirine AUC were 98 to 99%. In the third study, more patients rated the 200-mg than the 100-mg tablets as acceptable to swallow (70% vs. 43%). CONCLUSIONS: Comparable etravirine exposures were observed regardless of formulation or method of administration (i.e., dispersion); 200-mg tablets were rated as easier to swallow than 100-mg tablets.