Endocrine profile of the kisspeptin receptor agonist MVT-602 in healthy premenopausal women with and without ovarian stimulation: results from 2 randomized, placebo-controlled clinical tricals.

BACKGROUND: Kisspeptin is an essential regulator of hypothalamic gonadotropin-releasing hormone release and is required for physiological ovulation. Native kisspeptin-54 can induce oocyte maturation during in vitro fertilization treatment, including in women who are at high risk of ovarian hyperstimulation syndrome. MVT-602 is a potent kisspeptin receptor agonist with prospective utility to treat anovulatory disorders by triggering oocyte maturation and ovulation during medically assisted reproduction (MAR). Currently, the endocrine profile of MVT-602 during ovarian stimulation is unreported. OBJECTIVE: To determine the endocrine profile of MVT-602 in the follicular phase of healthy premenopausal women (phase-1 trial), and after minimal ovarian stimulation to more closely reflect the endocrine milieu encountered during MAR (phase-2a trial). DESIGN: Two randomized, placebo-controlled, parallel-group, dose-finding trials. SETTING: Clinical trials unit. PATIENTS: Healthy women aged 18-35 years, either without (phase-1; n = 24), or with ovarian stimulation (phase-2a; n = 75). INTERVENTIONS: Phase-1: single subcutaneous dose of MVT-602 (0.3, 1.0, or 3.0 µg) or placebo, (n = 6 per dose). Phase-2a: single subcutaneous dose of MVT-602 (0.1, 0.3, 1.0, or 3.0 µg; n = 16-17 per dose), triptorelin 0.2 mg (n = 5; active comparator), or placebo (n = 5). MAIN OUTCOME MEASURES: Phase-1: safety/tolerability; pharmacokinetics; and pharmacodynamics (luteinizing hormone [LH] and other reproductive hormones). Phase-2a: safety/tolerability; pharmacokinetics; pharmacodynamics (LH and other reproductive hormones); and time to ovulation assessed by transvaginal ultrasound. RESULTS: In both the trials, MVT-602 was safe and well tolerated across the entire dose range. It was rapidly absorbed and eliminated, with a mean elimination half-life of 1.3-2.2 hours. In the phase-2a trial, LH concentrations increased dose dependently; mean maximum change from baseline of 82.4 IU/L at 24.8 hours was observed after administration of 3 µg MVT-602 and remained >15 IU/L for 33 hours. Time to ovulation after drug administration was 3.3-3.9 days (MVT-602), 3.4 days (triptorelin), and 5.5 days (placebo). Ovulation occurred within 5 days of administration in 100% (3 µg), 88% (1 µg), 82% (0.3 µg), and 75% (0.1 µg), of women after MVT-602, 100% after triptorelin and 60% after placebo. CONCLUSIONS: MVT-602 induces LH concentrations of similar amplitude and duration as the physiological midcycle LH surge with potential utility for induction of oocyte maturation and ovulation during MAR. CLINICAL TRIAL REGISTRATION NUMBER: EUDRA-CT: 2017-003812-38, 2018-001379-20.

A Randomized Open-Label Study of Relugolix Alone or Relugolix Combination Therapy in Premenopausal Women.

BACKGROUND AND OBJECTIVE: Relugolix is a gonadotropin-releasing hormone receptor antagonist. Relugolix 40-mg monotherapy is associated with vasomotor symptoms and long-term bone mineral density loss due to hypoestrogenism. This study assessed whether the addition of estradiol (E2) 1 mg and norethindrone acetate (NETA) 0.5 mg to relugolix 40 mg (relugolix combination therapy) provides systemic E2 concentrations in the 20-50 pg/mL range to minimize these undesirable effects. METHODS: This was a randomized, open-label, parallel-group study to assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of relugolix 40 mg alone or in combination with E2 1 mg and NETA 0.5 mg in healthy premenopausal women. Eligible women were randomized 1:1 to receive relugolix alone or relugolix plus E2/NETA for 6 weeks. Study assessments included pharmacokinetic parameters of E2, estrone, and relugolix in both treatment groups, and norethindrone in the relugolix plus E2/NETA treatment group at weeks 3 and 6. RESULTS: Median E2 24 h average concentrations with the relugolix plus E2/NETA group (N = 23) were 31.5 pg/mL, 26 pg/mL higher compared with the relugolix-alone group (6.2 pg/mL) (N = 25). There were 86.4% of participants in the relugolix plus E2/NETA group who had E2 average concentrations exceeding 20 pg/mL, the threshold expected to minimize bone mineral density loss, compared with 21.1% in the relugolix-alone group. Both treatments were generally safe and well tolerated. CONCLUSIONS: Relugolix 40 mg in combination with E2 1 mg and NETA 0.5 mg provided systemic E2 concentrations within a range expected to minimize the risk of undesirable effects of hypoestrogenism associated with the administration of relugolix alone. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier no. NCT04978688. Trial registration date: 27 July, 2021; retrospectively registered.

Development of relugolix combination therapy as a medical treatment option for women with uterine fibroids or endometriosis.

Treatment of uterine fibroids (UF) and endometriosis (EM) has relied on the surgical skills of gynecologists to improve symptoms and potentially alter the course of these debilitating diseases. Medical management of symptoms for both diseases leverages combined hormonal contraceptives used off label as a first-line treatment, with nonsteroid anti-inflammatory drugs and opioids to manage pain as needed. Gonadotropin-releasing hormone (GnRH) receptor agonists (peptide analogs) have been used as short-term therapy to manage severe symptoms of UF or EM, treat anemia, and reduce fibroid size before surgery. The introduction of oral GnRH receptor antagonists opened the door for the development of new treatment options for UF, EM, and other estrogen-driven diseases. Relugolix is an orally active, nonpeptide, GnRH receptor antagonist that competitively binds to GnRH receptors, preventing the release of follicle-stimulating hormone and luteinizing hormone (LH) into the systemic circulation. In women, the reduction in follicle-stimulating hormone concentrations prevents natural follicular development, suppressing ovarian production of estrogen, and together with reductions in LH concentrations, prevent ovulation, corpus luteum formation, and, thereby, the production of progesterone (P). By reducing circulating concentrations of estradiol (E2) and P, relugolix improves heavy menstrual bleeding and other symptoms associated with UF and moderate to severe pain associated with EM, including dysmenorrhea, nonmenstrual pelvic pain (NMPP) and dyspareunia. However, as monotherapy, the use of relugolix is associated with signs and symptoms of a hypoestrogenic state, including bone mineral density loss and vasomotor symptoms. The clinical development of relugolix incorporated the addition of a 1 mg dose of E2 and a 0.5-mg dose of norethindrone acetate (NETA) to achieve systemic E2 concentrations that remain in a therapeutic range while mitigating the risk for bone mineral density loss and vasomotor symptoms, enabling the longer-term treatment and reducing the impact of symptoms on quality of life, and potentially delaying or preventing the need for surgery. Relugolix 40 mg in combination with estradiol (E2) 1 mg and NETA 0.5 mg as a single fixed-dose combination tablet (relugolix combination therapy [relugolix-CT]) approved in the United States as MYFEMBREE is the first and only once daily oral GnRH antagonist combination therapy indicated for the management of heavy menstrual bleeding associated with UF and moderate to severe pain associated with EM. In the European Union (EU) and the United Kingdom (UK), relugolix-CT is approved as RYEQO for the management of symptoms associated with UF. In Japan, relugolix 40 mg, as monotherapy, was the first GnRH receptor antagonist approved to improve symptoms associated with UF or pain associated with EM under the brand name RELUMINA. In men, relugolix suppresses testosterone production. Relugolix 120 mg (ORGOVYX) was developed by Myovant Sciences and is approved in the United States, EU, and UK as the first and only oral androgen-deprivation therapy for the treatment of advanced prostate cancer. This review is focused on the development of relugolix and relugolix-CT in women's health indications.

A Phase I Clinical Trial Evaluating the Safety and Dosing of Relugolix with Novel Hormonal Therapy for the Treatment of Advanced Prostate Cancer.

BACKGROUND: Androgen deprivation therapy (ADT), a cornerstone of prostate cancer treatment, is commonly co-prescribed as combination therapy. OBJECTIVE: To better understand the safety and tolerability profile of relugolix, an oral non-peptide gonadotropin-releasing hormone (GnRH) receptor antagonist, in combination with abiraterone acetate (abiraterone) and apalutamide, a phase I study was undertaken. PATIENTS AND METHODS: This is an ongoing, 52-week, open-label, parallel cohort study of relugolix in combination with abiraterone in men with metastatic castration-sensitive prostate cancer (mCSPC) or metastatic castration-resistant prostate cancer (mCRPC) [Part 1] and apalutamide in men with mCSPC or non-metastatic castration-resistant prostate cancer (nmCRPC) [Part 2]. Eligible patients treated with leuprolide acetate or degarelix with abiraterone or apalutamide prior to baseline, at which time they were transitioned to relugolix. Assessments included reporting of adverse events, clinical laboratory tests, vital sign measurements, electrocardiogram (ECG) parameters, and testosterone serum concentrations. In this interim report, patients completing ≥12 weeks were included. RESULTS: Overall, 15 men were enrolled in Part 1 and 10 in Part 2. Adverse events were mostly mild-to-moderate in intensity and were consistent with the known safety profiles of the individual medications. No transition (from prior ADT treatment)- or time-related trends in clinical laboratory tests, vital sign measurements, or ECG parameters were observed. Mean testosterone concentrations remained below castration levels. CONCLUSIONS: Combination therapy of relugolix and abiraterone or apalutamide was associated with a favorable safety and tolerability profile consistent with the known profiles of the individual medications. Castration levels of testosterone were maintained after transitioning to relugolix from other ADTs. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04666129.

Population PK and Semimechanistic PK/PD Modeling and Simulation of Relugolix Effects on Testosterone Suppression in Men with Prostate Cancer.

Relugolix, the first orally active, nonpeptide gonadotropin-releasing hormone receptor antagonist, is approved in the United States and the European Union for the treatment of adult patients with advanced prostate cancer. The recommended dosing regimen is a 360-mg loading dose followed by a 120-mg daily dose. Relugolix and testosterone concentration data and clinical information from two phase I studies, two phase II studies, and the phase III safety and efficacy study (HERO) were used to develop a population pharmacokinetic (PopPK) model and a semimechanistic population pharmacokinetic/pharmacodynamic (PopPK/PD) model that characterized relugolix exposure and its relationship to testosterone concentrations. Age, body weight, and Black/African American race had at most minimal effects on relugolix exposure or testosterone concentrations with no clinical relevance. Simulations using the PopPK/PD model confirmed the recommended dosing regimen of relugolix, with the median simulated testosterone concentrations predicted to achieve castration levels (< 50 ng/dL) and profound castration levels (< 20 ng/dL) by day 2 and day 9, respectively, and demonstrated that 97.3% and 85.5% of the patients remained at castration levels (< 50 ng/dL) upon temporary interruption of treatment for 7 days and 14 days, respectively. Collectively, simulations based on the PopPK and PopPK/PD models were consistent with actual data from clinical studies, reflecting the high predictiveness of the models and supporting the reliability of model-based simulations. These models can be used to provide guidance regarding dosing recommendations under various circumstances (e.g., temporary interruption of treatment, if needed) for relugolix.

Effect of Cefiderocol, a Siderophore Cephalosporin, on QT/QTc Interval in Healthy Adult Subjects.

PURPOSE: Cefiderocol is a novel siderophore cephalosporin with potent activity against gram-negative bacteria, including multidrug-resistant strains. This Phase I study was conducted to assess the tolerability of single-ascending doses of cefiderocol (part 1) and the effect of cefiderocol on cardiac repolarization, assessed using the electrocardiographic corrected QT interval (QTcF) and other ECG parameters (part 2), in healthy adult subjects. METHODS: Part 1 was a randomized, double-blind, placebo-controlled, single-ascending dose study in healthy adult male and female subjects. Part 2 was a 4-period crossover study in which subjects received a single 2-g dose of cefiderocol (therapeutic dose), a single 4-g dose of cefiderocol (supratherapeutic dose), or saline (placebo), each infused over 3 hours, and a single oral 400-mg dose of moxifloxacin. In each treatment period, continuous cardiac monitoring was used to assess the effects of cefiderocol on ECG parameters. The QT interval corrected using the Fridericia formula (QTcF) was the primary ECG parameter; the time-matched placebo- and baseline-adjusted (dd)-QTcF interval was the primary end point. The plasma pharmacokinetic properties of cefiderocol were calculated on the basis of concentration-time profiles in all evaluable subjects. FINDINGS: All point estimates for the ddQTcF interval were <5 ms and the upper bound of the 90% CIs were <10 ms at each timepoint after the initiation of the cefiderocol 3-hour infusion. Concentration-effect modeling showed a slightly negative slope and predicted modestly negative values of the ddQTcF interval at the Cmax of cefiderocol. Both doses of cefiderocol were well tolerated. All adverse events were mild in severity, with no deaths or serious adverse events reported. IMPLICATIONS: Overall, therapeutic and supratherapeutic doses of cefiderocol had no apparent clinically significant effect on the QTcF.

Population Pharmacokinetic Modeling to Evaluate Standard Magnesium Sulfate Treatments and Alternative Dosing Regimens for Women With Preeclampsia.

Magnesium sulfate is the standard therapy for prevention and treatment of eclampsia. Two standard dosing regimens require either continuous intravenous infusion or frequent, large-volume intramuscular injections, which may preclude patients from receiving optimal care. This project sought to identify alternative, potentially more convenient, but similarly effective dosing regimens that could be used in restrictive clinical settings. A 2-compartment population pharmacokinetic (PK) model was developed to characterize serial PK data from 92 pregnant women with preeclampsia who received magnesium sulfate. Body weight and serum creatinine concentration had a significant impact on magnesium PK. The final PK model was used to simulate magnesium concentration profiles for the 2 standard regimens and several simplified alternative dosing regimens. The simulations suggest that intravenous regimens with loading doses of 8 g over 60 minutes followed by 2 g/h for 10 hours and 12 g over 120 minutes followed by 2 g/h for 8 hours (same total dose as the standard intravenous regimen but shorter treatment duration) would result in magnesium concentrations below the toxic range. For the intramuscular regimens, higher maintenance doses given less frequently (4 g intravenously + 10-g intramuscular loading doses with maintenance doses of 8 g every 6 hours or 10 g every 8 hours for 24 hours) or removal of the intravenous loading dose (eg, 10 g intramusculary every 8 hours for 24 hours) may be reasonable alternatives. In addition, individualized dose adjustments based on body weight and serum creatinine were proposed for the standard regimens.

Sitagliptin, a dipeptidyl peptidase-4 inhibitor, does not affect the pharmacokinetics of ethinyl estradiol or norethindrone in healthy female subjects.

Sitagliptin is a dipeptidyl peptidase-IV (DPP-4) inhibitor used for the treatment of patients with type 2 diabetes mellitus. This randomized, placebo-controlled, 2-period, crossover study evaluated the effect of sitagliptin on the pharmacokinetics of 17 α-ethinyl estradiol (EE(2)) and norethindrone (NET) in healthy female subjects who were receiving oral contraceptives for >3 months prior to enrollment. A total of 18 subjects with normal menstrual cycles received the oral contraceptive pill ORTHO-NOVUM(®) 7/7/7 on days 1 to 28 for 2 successive cycles, and on days 1 to 21 were randomly assigned to receive sitagliptin 200 mg/day (2 × 100 mg tablets) or placebo using a computer-generated allocation schedule. Blood samples for determination of plasma EE(2) and NET concentrations were collected predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours postdose on day 20 or 21 of each treatment period. The GMRs (90% confidence interval [CI]) for the AUC(0-24 hr) of EE(2) and NET were 0.99 (0.93, 1.06) and 1.03 (0.97, 1.09), respectively, and for C(max) were 0.97 (0.86, 1.10) and 0.98 (0.89, 1.07), respectively. The coadministration of sitagliptin 200 mg/day with an oral contraceptive for 21 days did not lead to clinically meaningful alterations in the pharmacokinetics of EE(2) and NET.

Safety and pharmacokinetics of higher doses of caspofungin in healthy adult participants.

Caspofungin was the first in a new class of antifungal agents (echinocandins) indicated for the treatment of primary and refractory fungal infections. Higher doses of caspofungin may provide another option for patients who have failed caspofungin or other antifungal therapy. This study evaluated the safety, tolerability, and pharmacokinetics of single 150- and 210-mg doses of caspofungin in 16 healthy participants and 100 mg/d for 21 days in 20 healthy participants. Other than infusion site reactions and 1 reversible elevation in alanine aminotransferase (≥2× and <4× upper limit of normal), caspofungin was generally well tolerated. Geometric mean AUC(0-∞) after single 150- and 210-mg doses was 279.7 and 374.9 µg·h/mL, respectively; peak concentrations were 29.4 and 33.5 µg/mL, respectively; and 24-hour postdose concentrations were 2.8 and 4.2 µg/mL, respectively. Steady state was achieved in the third week of dosing. Following multiple 100-mg doses of caspofungin, day 21 geometric mean AUC(0-24) was 227.4 µg·h/mL, peak concentration was 20.9 µg/mL, and trough concentration was 4.7 µg/mL. Beta-phase t(1/2) was ~8 to ~13 hours. Caspofungin pharmacokinetics at these higher doses were dose proportional to and consistent with those observed at lower doses, suggesting a modest nonlinearity of increased accumulation with dose, which was considered not clinically meaningful.

Bioequivalence of sitagliptin/metformin fixed-dose combination tablets and concomitant administration of sitagliptin and metformin in healthy adult subjects: a randomized, open-label, crossover study.

BACKGROUND: Treatment with an oral antihyperglycaemic agent administered as monotherapy is often unsuccessful at achieving or maintaining glycaemic control in patients with type 2 diabetes mellitus. The combined use of sitagliptin and metformin is an effective treatment for type 2 diabetes mellitus, consistent with the complementary mechanisms of action by which these two agents improve glucose control. OBJECTIVES: To establish bioequivalence between sitagliptin/metformin fixed-dose combination (FDC) tablets (Janumet®) and co-administration of corresponding doses of sitagliptin and metformin as individual tablets. METHODS: This was an randomized, open-label, two-part, two-period crossover study, which included a total of 48 healthy subjects, 24 subjects per part (parts I and II). Within each part, subjects were assigned to receive treatments in random order; treatment periods were separated by a washout interval of at least 7 days. Eligible study participants included healthy, non-smoking (within previous 6 months), male and female subjects aged between 18 and 45 years with a body mass index ≤32 kg/m². Part I consisted of treatments A (co-administration of sitagliptin 50 mg and metformin 500 mg) and B (sitagliptin/metformin 50 mg/500 mg FDC tablet); part II consisted of treatments C (co-administration of sitagliptin 50 mg and metformin 1000 mg) and D (sitagliptin 50 mg/metformin 1000 mg FDC tablet). Blood samples were collected pre-dose and up to 72 hours post-dose in each treatment period for determination of plasma sitagliptin and metformin concentrations and calculation of the respective pharmacokinetic parameters. The area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) and the maximum plasma concentration (C(max)) for both sitagliptin and metformin were designated as the primary and secondary study endpoints, respectively, and analysed using an ANOVA model after logarithmic transformation of the data. Bioequivalence was established if the 90% confidence intervals (CIs) for the geometric mean ratios (GMRs; FDC tablet/co-administration) of the AUC(∞) and C(max) for both sitagliptin and metformin fell within pre-specified bounds of (0.80, 1.25). RESULTS: The GMRs (90% CI) for the AUC(∞) of sitagliptin 50 mg and metformin 500 mg were 0.98 (0.96, 1.00) and 1.0 (0.95, 1.04), respectively, and for C(max) of sitagliptin and metformin were 1.00 (0.94, 1.06) and 1.00 (0.94, 1.06), respectively. The GMRs (90% CI) for the AUC(∞) of sitagliptin 50 mg and metformin 1000 mg (part II) were 0.97 (0.95, 0.99) and 1.00 (0.94, 1.07), respectively, and for the C(max) of sitagliptin and metformin were 0.94 (0.88, 1.01) and 1.01 (0.93, 1.10), respectively. In both part I and part II, the 90% CIs of the GMRs of the AUC(∞) and C(max) for both sitagliptin and metformin all fell within the pre-specified bioequivalence bounds of (0.80, 1.25). Administration of single doses of sitagliptin/metformin 50 mg/500 mg (part I) and 50 mg/1000 mg FDC tablets (part II) and co-administration of corresponding doses of sitagliptin and metformin as individual tablets were generally well tolerated. CONCLUSION: The sitagliptin/metformin 50 mg/500 mg and 50 mg/1000 mg FDC tablets are bioequivalent to co-administration of corresponding doses of sitagliptin and metformin as individual tablets and support bioequivalence to the sitagliptin/metformin 50 mg/850 mg tablet strength. These results indicate that the safety and efficacy profile of co-administration of sitagliptin and metformin can be extended to the sitagliptin/metformin FDC tablets.

Bioequivalence of the 4-mg Oral Granules and Chewable Tablet Formulations of Montelukast.

PURPOSE: The primary objective of the studies was to demonstrate bioequivalence between the oral granules formulation and chewable tablet of montelukast in the fasted state. Effect of food on the pharmacokinetics of the oral granules was also evaluated. METHODS: The Formulation Biocomparison Study (Study 1) and the Final Market Image Study (Study 2) each used an open-label, randomized, 3-period crossover design where healthy adult subjects (N = 24 and 30, respectively) received montelukast as a single 4-mg dose of the oral granules formulation and a 4-mg chewable tablet fasted, and a single 4-mg dose of the oral granules formulation with food (on 2 teaspoons of applesauce [Study 1] or after consumption of a high-fat breakfast [Study 2]). The formulations were to be considered bioequivalent if the 90% confidence intervals (CIs) for geometric mean ratios (GMRs) (oral granules/chewable tablet) for the AUC(0-infinity) and C(max) of montelukast were within the prespecified comparability bounds of (0.80, 1.25). For the food-effect assessment in Study 1, comparability bounds were prespecified as (0.50, 2.00) only for the 90% CI of the GMR (oral granules fed/oral granules fasted) for the AUC(0-infinity) of montelukast; the 90% CI of the GMR for the C(max) of montelukast, however, also was computed. In Study 2, 90% CIs of the GMRs (oral granules fed/oral granules fasted) for the AUC(0-infinity) and C(max) of montelukast were computed; comparability bounds were not prespecified. RESULTS: Comparing the exposure of the formulations, the 90% CIs of the GMRs for AUC(0-infinity) and C(max) were within the prespecified bound of (0.80, 1.25). For AUC(0-infinity), the GMRs (90% CI) for Study 1 and Study 2 were 1.01 (0.92, 1.11) and 0.95 (0.91, 0.99), respectively. For C(max), respective values were 0.99 (0.86, 1.13) and 0.92 (0.84, 1.01). When the oral granules formulation was administered with food, 90% CIs of the GMRs for both AUC(0-infinity) and C(max) in both studies were contained within the interval of (0.50, 2.00). CONCLUSIONS: The 4-mg oral granules and 4-mg chewable tablet formulations of montelukast administered in the fasted state are bioequivalent. Single 4-mg doses of the oral granules formulation and the chewable tablet of montelukast are generally well tolerated.

Effect of moderate hepatic insufficiency on the pharmacokinetics of sitagliptin.

BACKGROUND: Sitagliptin is a highly selective dipeptidyl peptidase-4 inhibitor for the treatment of patients with type 2 diabetes. Sitagliptin is primarily excreted by renal elimination as unchanged drug, with only a small percentage (approximately 16%) undergoing hepatic metabolism. OBJECTIVES: The primary purpose of this study was to evaluate the influence of moderate hepatic insufficiency on the pharmacokinetics of sitagliptin. METHODS: In an open-label study, a single 100-mg oral dose of sitagliptin was administered to 10 male or female patients with moderate hepatic insufficiency (Child-Pugh's scores ranged from 7 to 9) and 10 healthy control subjects matched to each patient for race, gender, age (+/- 5 yrs) and body mass index (BMI kg/m2 +/- 5%). After administration of each dose, blood and urine samples were collected to assess sitagliptin pharmacokinetics. RESULTS: The mean AUC(0-infinity) and Cmax for sitagliptin were numerically, but not significantly (p>0.050), higher in patients with moderate hepatic insufficiency compared with healthy matched control subjects by 21% and 13%, respectively. These slight differences were also not considered to be clinically meaningful. Moderate hepatic insufficiency had no statistically significant effect on the Tmax, apparent terminal t(1/2), fraction of the oral dose excreted into urine (f(e,0-infinity)) and renal clearance (ClR) (p>0.100) of sitagliptin. Sitagliptin was generally well tolerated by both patients and subjects; all adverse experiences were transient and rated as mild in intensity. CONCLUSIONS: Moderate hepatic insufficiency has no clinically meaningful effect on the pharmacokinetics of sitagliptin.

Pharmacokinetics and safety of montelukast oral granules in children 1 to 3 months of age with bronchiolitis.

The single-dose pharmacokinetics of montelukast 4-mg oral granules and tolerability of daily administration of 2 different doses of montelukast (4 mg and 8 mg given once daily for 7 days) versus placebo were evaluated in 12 infants 1 to 3 months of age with bronchiolitis or a history of bronchiolitis and asthma-like symptoms. The population area under the concentration-time curve estimate after a single 4-mg dose of montelukast was 13 195.7 +/- 2309.8 (standard error) ng.hr/mL, 3.6 times higher than historical values in infants 3 to 24 months of age. Six patients had 10 total clinical adverse experiences; none was considered serious or drug related. Three patients had transient drug-related increases in aspartate aminotransferase (montelukast 8 mg [n = 2]; placebo [n = 1]). Despite increased systemic exposure after administration of a single dose of montelukast 4-mg oral granules in infants 1 to 3 months of age compared with that in pediatric patients 3 to 24 months of age, administration of montelukast at 4 and 8 mg once daily for 7 days in 1- to 3-month-old infants was generally well tolerated.

Single- and multiple-dose administration of caspofungin in patients with hepatic insufficiency: implications for safety and dosing recommendations.

This report investigated safety and dosing recommendations of intravenous caspofungin in hepatic insufficiency. In the single-dose study, 8 patients each with mild and moderate hepatic insufficiency received 70 mg of caspofungin. In the multiple-dose study, 8 patients with mild hepatic insufficiency and 13 healthy matched controls received 70 mg on day 1 and 50 mg daily on days 2 through 14. Eight patients with moderate hepatic insufficiency received 70 mg on day 1 and 35 mg daily on days 2 through 14. Caspofungin was generally well tolerated with no discontinuations due to serious or nonserious adverse experiences. The area under the concentration-time profile over the interval of last quantifiable point to infinity (AUC(0-infinity)) geometric mean ratio (GMR) (90% confidence interval [CI]) for mild hepatic insufficiency/historical controls was 1.55 (1.32-1.86) in the single-dose study and for mild hepatic insufficiency/concurrent controls was 1.21 (1.04-1.39) for day 14 area under the concentration-time profile calculated over the interval 0 to 24 hours (AUC(0-24h)) following multidose. The AUC(0-infinity) GMR (90% CI) for moderate hepatic insufficiency/historical controls was 1.76 (1.51-2.06) following 70 mg; AUC(0-24h) GMR (90% CI) for moderate hepatic insufficiency/concurrent controls was 1.07 (0.90-1.28) on day 14 after 35 mg daily. No dosage adjustment is recommended for patients with mild hepatic insufficiency. A dosage reduction to 35 mg daily following the 70-mg loading dose is recommended for patients with moderate hepatic insufficiency.

Pharmacokinetics and safety of montelukast in children aged 3 to 6 months.

The single-dose population estimate of the area under the concentration-time curve (AUC(pop)) from time zero to infinity (AUC(0-infinity)), maximum plasma concentration (C(max)), and time to C(max) (t(max)) of montelukast 4-mg oral granules were investigated in infants aged 3 to 6 months. Montelukast concentrations were quantitated after a single 4-mg dose of montelukast oral granules. Pharmacokinetic parameters were determined using a population-based approach with a nonlinear mixed-effect, 1-compartment model with first-order absorption and elimination. Ninety-five percent confidence intervals for the AUC(pop) ratio (3 to 6 months/6 to 24 months) were determined. Safety and tolerability were assessed. Montelukast 4-mg oral granules in children 3 to 6 months of age yielded systemic exposure (AUC(pop) = 3644.3 +/- 481.5 ng x h/mL) similar to that observed in children aged 6 to 24 months (3226.6 +/- 250.0 ng x h/mL). Systemic exposure after a 4-mg dose of montelukast as oral granules is similar in children aged 3 to 6 months and 6 to 24 months.

A comparison of nonlinear mixed-model analyses for a pediatric pharmacokinetic study.

Nonlinear mixed models are important tools for analyzing repeated measures data. In particular, these models are used for population pharmacokinetic analyses for estimating population pharmacokinetic parameters. As more clinical studies are performed for the advancement of treatment of pediatric patients, methodology is needed for comparing results from pharmacokinetic studies in pediatric patients and adult control groups. These pediatric studies introduce complexities to the design and analysis, including how analysis of sparse data affects the limitations of model selection. A case study is presented demonstrating that good communication with regulatory agencies and appropriate selection of analysis models are integral parts of completing population analyses for timely approval and labeling of drugs for treating pediatric patients.

A population pharmacokinetic model for montelukast disposition in adults and children.

PURPOSE: The purpose was to develop a population pharmacokinetic model for montelukast after intravenous administration. Clinical trial simulations were conducted using the model developed to identify the lowest intravenous dose in 6- to 14-year-old children that would give montelukast systemic exposures that were comparable to those found to be associated with efficacy in adults. METHODS: Two clinical studies were conducted where montelukast was administered intravenously as a 7-mg dose to adults and as a 3.5-mg dose to children aged 6 to 14 years. Model development included defining the base pharmacostatistical model and investigating the effects of demographic variables [age and total body weight (TBW)] on the structural parameters, using a nonlinear mixed effect modeling approach. RESULTS: A linear three-compartment pharmacokinetic model was found to best describe the disposition of montelukast. Inclusion of TBW as a covariate caused a 35% and 63% decrease in the interindividual variabilities on clearance and central volume of distribution, respectively. Trial simulations suggested that a 5.25-mg intravenous dose of montelukast should be chosen in children aged 6 to 14 years. CONCLUSIONS: The model developed can adequately describe the intravenous pharmacokinetics of montelukast and can be used as a useful tool for dose selection in pediatric subpopulations.

Potential for interactions between caspofungin and nelfinavir or rifampin.

The potential for interactions between caspofungin and nelfinavir or rifampin was evaluated in two parallel-panel studies. In study A, healthy subjects received a 14-day course of caspofungin alone (50 mg administered intravenously [IV] once daily) (n = 10) or with nelfinavir (1,250 mg administered orally twice daily) (n = 9) or rifampin (600 mg administered orally once daily) (n = 10). In study B, 14 subjects received a 28-day course of rifampin (600 mg administered orally once daily), with caspofungin (50 mg administered IV once daily) coadministered on the last 14 days, and 12 subjects received a 14-day course of caspofungin alone (50 mg administered IV once daily). The coadministration/administration alone geometric mean ratio for the caspofungin area under the time-concentration profile calculated for the 24-h period following dosing [AUC(0-24)] was as follows (values in parentheses are 90% confidence intervals [CIs]): 1.08 (0.93-1.26) for nelfinavir, 1.12 (0.97-1.30) for rifampin (study A), and 1.01 (0.91-1.11) for rifampin (study B). The shape of the caspofungin plasma profile was altered by rifampin, resulting in a 14 to 31% reduction in the trough concentration at 24 h after dosing (C(24h)), consistent with a net induction effect at steady state. Both the AUC and the C(24h) were elevated in the initial days of rifampin coadministration in study A (61 and 170% elevations, respectively, on day 1) but not in study B, consistent with transient net inhibition prior to full induction. The coadministration/administration alone geometric mean ratio for the rifampin AUC(0-24) on day 14 was 1.07 (90% CI, 0.83-1.38). Nelfinavir does not meaningfully alter caspofungin pharmacokinetics. Rifampin both inhibits and induces caspofungin disposition, resulting in a reduced C(24h) at steady state. An increase in the caspofungin dose to 70 mg, administered daily, should be considered when the drug is coadministered with rifampin.

Pharmacokinetics of montelukast in asthmatic patients 6 to 24 months old.

Montelukast is a cysteinyl leukotriene receptor antagonist approved for the treatment of asthma for those ages 1 year old to adult. The purpose of this study was to evaluate the pharmacokinetic comparability of a 4-mg dose of montelukast oral granules in patients > or = 6 to < 24 months old to the 10-mg approved dose in adults. This was an open-label study in 32 patients. Population pharmacokinetic parameters included estimates of AUC(pop), C(max), and t(max). Results were compared with estimates from adults (10-mg film-coated tablet [FCT]). Dose selection criteria were for the 95% confidence interval (CI) for the AUC(pop) estimate ratio (pediatric/adult 10 mg FCT) to be within comparability bounds of (0.5, 2.00). The AUC(pop) ratio and the 95% CI for children compared with adults were within the predefined comparability bounds. Observed plasma concentrations were also similar. Based on systemic exposure of montelukast, a 4-mg dose of montelukast appears appropriate for children as young as 6 months of age.

Disposition of caspofungin: role of distribution in determining pharmacokinetics in plasma.

The disposition of caspofungin, a parenteral antifungal drug, was investigated. Following a single, 1-h, intravenous infusion of 70 mg (200 microCi) of [(3)H]caspofungin to healthy men, plasma, urine, and feces were collected over 27 days in study A (n = 6) and plasma was collected over 26 weeks in study B (n = 7). Supportive data were obtained from a single-dose [(3)H]caspofungin tissue distribution study in rats (n = 3 animals/time point). Over 27 days in humans, 75.4% of radioactivity was recovered in urine (40.7%) and feces (34.4%). A long terminal phase (t(1/2) = 14.6 days) characterized much of the plasma drug profile of radioactivity, which remained quantifiable to 22.3 weeks. Mass balance calculations indicated that radioactivity in tissues peaked at 1.5 to 2 days at approximately 92% of the dose, and the rate of radioactivity excretion peaked at 6 to 7 days. Metabolism and excretion of caspofungin were very slow processes, and very little excretion or biotransformation occurred in the first 24 to 30 h postdose. Most of the area under the concentration-time curve of caspofungin was accounted for during this period, consistent with distribution-controlled clearance. The apparent distribution volume during this period indicated that this distribution process is uptake into tissue cells. Radioactivity was widely distributed in rats, with the highest concentrations in liver, kidney, lung, and spleen. Liver exhibited an extended uptake phase, peaking at 24 h with 35% of total dose in liver. The plasma profile of caspofungin is determined primarily by the rate of distribution of caspofungin from plasma into tissues.