Effect of raltegravir on estradiol and norgestimate plasma pharmacokinetics following oral contraceptive administration in healthy women.

AIMS: Oral contraceptives such as norgestimate-ethinyl estradiol (Ortho Tri-Cyclen®) are commonly prescribed in the HIV-infected patient population. A placebo-controlled, randomized, two-period crossover study in healthy HIV-seronegative subjects was conducted to assess the effect of raltegravir on the pharmacokinetics of the estrogen and progestin components of norgestimate-ethinyl estradiol [ethinyl estradiol (EE) and norelgestromin (NGMN), an active metabolite of norgestimate (NGT)]. METHODS: In each of two periods, nineteen healthy women established on norgestimate-ethinyl estradiol contraception (21 days of active contraception; 7 days of placebo) received either 400 mg raltegravir or matching placebo twice daily on days 1-21. Pharmacokinetics were analysed on day 21 of each period. RESULTS: The geometric mean ratio (GMR) and 90% confidence interval (CI) for the EE component of norgestimate-ethinyl estradiol when co-administrated with raltegravir relative to EE alone was 0.98 (0.93-1.04) for the area under the concentration-time curve from 0 to 24 h (AUC(0-24 h) ) and 1.06 (0.98-1.14) for the maximum concentration of drug in the plasma (C(max) ); the GMR (90% CI) for the NGMN component of norgestimate-ethinyl estradiol when co-administered with raltegravir relative to NGMN alone was 1.14 (1.08-1.21) for AUC(0-24 h) and 1.29 (1.23-1.37) for C(max) . There were no discontinuations due to a study drug-related adverse experience, nor any serious clinical or laboratory adverse experience. CONCLUSIONS: Raltegravir has no clinically important effect on EE or NGMN pharmacokinetics. Co-administration of raltegravir and an oral contraceptive containing EE and NGT was generally well tolerated; no dose adjustment is required for oral contraceptives containing EE and NGT when co-administered with raltegravir.

Assessment of a pharmacokinetic and pharmacodynamic interaction between simvastatin and anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.

AIMS: Anacetrapib is an orally active, potent inhibitor of cholesteryl ester transfer protein (CETP), which is in development for the treatment of dyslipidaemia. Because of the likely use of anacetrapib with hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, we aimed to evaluate the potential for a pharmacokinetic interaction with simvastatin. METHODS: A randomized, two-period, two-treatment, balanced, open-label, crossover study in 12 healthy subjects was performed. Subjects received simvastatin 40 mg alone or anacetrapib 150 mg co-administered with simvastatin 40 mg, once daily. Both treatments were administered following a low-fat breakfast for 14 days, separated by a wash-out period of at least 14 days. Safety and tolerability, simvastatin and simvastatin acid concentrations, and lipoproteins, were assessed. RESULTS: Both treatments were well tolerated. The pharmacokinetics of simvastatin and simvastatin acid were similar with and without anacetrapib administration {AUC(0-24 h) geometric mean ratio [90% confidence interval (CI)] for simvastatin acid and simvastatin were 1.36 [1.17, 1.57] and 1.30 [1.14, 1.47], respectively} based on the prespecified comparability bounds of (0.50, 2.00). Treatment with simvastatin alone led to a mean (95% CI) % reduction from baseline in low-density lipoprotein-cholesterol (LDL-C) of -36% (-27, -46) compared with a reduction of -54% (-44, -63) for anacetrapib co-administered with simvastatin. CONCLUSIONS: There appears to be no clinically meaningful effect of anacetrapib on the pharmacokinetic parameters of simvastatin. When co-administered with simvastatin, anacetrapib appeared to exhibit incremental LDL-C-lowering efficacy, due to CETP inhibition. Co-administration of anacetrapib and simvastatin was well tolerated.

Relative oral bioavailability of morphine and naltrexone derived from crushed morphine sulfate and naltrexone hydrochloride extended-release capsules versus intact product and versus naltrexone solution: a single-dose, randomized-sequence, open-label, three-way crossover trial in healthy volunteers.

BACKGROUND: Morphine sulfate/sequestered naltrexone hydrochloride (HCl) (MS-sNT) extended-release fixed-dose combination capsules, approved by the US Food and Drug Administration (FDA) in August 2009 for chronic moderate to severe pain, contain extended-release morphine pellets with a sequestered core of the opioid antagonist naltrexone. MS-sNT was designed so that if the product is tampered with by crushing, the naltrexone becomes bioavailable to mitigate morphine-induced subjective effects, rendering the product less attractive for tampering. OBJECTIVES: The primary aim of this study was to compare the oral bioavailability of naltrexone and its metabolite 6-beta-naltrexol, derived from crushed pellets from MS-sNT capsules, to naltrexone solution. This study also assessed the relative bioavailability of morphine from crushed pellets from MS-sNT capsules and that from the whole, intact product. METHODS: This single-dose, randomized-sequence, open-label, 3-period, 3-treatment crossover trial was conducted in healthy volunteers. Adults admitted to the study center underwent a 10-hour overnight fast before study drug administration. Each subject received all 3 of the following treatments, 1 per session, separated by a 14-day washout: tampered pellets (crushed for >or=2 minutes with a mortar and pestle) from a 60-mg MS-sNT capsule (60 mg morphine/2.4 mg naltrexone); 60-mg whole, intact MS-sNT capsule; and oral naltrexone HCl (2.4 mg) solution. Plasma concentrations of naltrexone and 6-beta-naltrexol were measured 0 to 168 hours after administration. Morphine pharmaco-kinetics of crushed and whole pellets were determined 0 to 72 hours after administration. The analysis of relative bioavailability was based on conventional FDA criteria for assuming bioequivalence; that is, 90% CIs for ratios of geometric means (natural logarithm [In]-transformed C(max) and AUC) fell within the range of 80% to 125%. Subjects underwent physical examinations, clinical laboratory tests, and ECG at screening and study discharge and were monitored for adverse events (AEs) throughout the study. RESULTS: Of the 24 subjects enrolled in the study, 23 completed it. Most subjects were white (79%) and male (63%); the mean (SD) age was 39.3 (11.2) years and the mean weight was 77.6 (13.5) kg (range, 55.0102.5 kg). Plasma C(max) and AUC(0-t) of naltrexone after the administration of crushed pellets of MS-sNT (579 pg/mL and 1811 h . pg/mL, respectively) and naltrexone solution (584 pg/mL and 1954 h . pg/mL) were not significantly different; 90% CIs were 83.8% to 116% and 83.3% to 102%, meeting the regulatory requirements for assuming bioequivalence in this study population. Plasma naltrexone concentration was below the lower limit of quantitation (4.0 pg/mL) in 23 of 24 subjects (96%) after whole MS-sNT administration. Morphine AUC(0-t) was not significantly different whether MS-sNT was crushed (163 h . ng/mL) or administered whole (174 h . ng/mL), but C(max) was numerically higher (24.5 vs 7.7 ng/mL) and T(max) was numerically shorter (2.00 vs 7.03 hours) with MS-sNT crushed versus whole. The most commonly reported AEs were nausea (8/23 [35%], 10/24 [42%], and 3/23 [13%] subjects in the crushed, whole, and naltrexone groups, respectively) and emesis (6 [26%], 7 [29%], and 2 [9%]). CONCLUSIONS: In this single-dose study, when pellets from MS-sNT were crushed, naltrexone appeared to be completely released and available to mitigate morphine-induced effects. When MS-sNT was administered whole, morphine was released in an extended-release fashion while naltrexone remained sequestered.

Relative bioavailability of sapropterin from intact and dissolved sapropterin dihydrochloride tablets and the effects of food: a randomized, open-label, crossover study in healthy adults.

BACKGROUND: Phenylketonuria (PKU) is an autosomal recessive metabolic disorder characterized by hyperphenylalaninemia in association with neurocognitive and neuromotor impairment. Sapropterin dihydrochloride (hereafter referred to as sapropterin) administered orally as dissolved tablets is approved by the US Food and Drug Administration for hyperphenylalaninemia in patients with tetrahydrobiopterin responsive PKU. OBJECTIVES: This study compared the relative oral bioavailability of sapropterin when administered as intact and dissolved tablets. It also assessed the effect of food on the oral bioavailability of sapropterin administered as intact tablets. METHODS: This was a randomized, open-label, 3-treatment, 6-sequence, 3-period crossover study in healthy male and female subjects. Subjects were randomized to receive single oral 10-mg/kg doses of sapropterin administered as dissolved tablets after a fast; as intact tablets after a fast; and as intact tablets with a high-calorie, high-fat meal. The 3 dosing periods were separated by a washout period of at least 7 days. In each dosing period, blood samples were obtained within 40 minutes before and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, and 24 hours after dosing. A follow-up assessment was performed 5 to 7 days after the last dosing period. The relative bioavailability of sapropterin from the 3 dosing regimens was assessed based on C(max), AUC(0-t), and AUC(0-infinity), estimated from calculated plasma tetrahydrobiopterin concentrations using a noncompartmental model. Safety assessments included physical examinations, clinical laboratory tests, and ECGs at the beginning and end of the study. Vital signs were monitored periodically during each treatment period. RESULTS: The study enrolled 32 healthy subjects (16 men, 16 women) with a mean (SD) age of 29.2 (9.0) years, height of 172.7 (10.0) cm, weight of 73.0 (13.9) kg, and body mass index ranging from 18 to 30 kg/m(2). Twenty-three were white, 5 African American, 2 Asian/Pacific Islander, 1 Hispanic, and 1 Native American. The estimated geometric mean ratio of AUC(0-t) for intact compared with dissolved tablets under fasting conditions was 141.24% (90% CI, 122.05-163.43), and the geometric mean ratio of AUC(0-t) for intact tablets under fed compared with fasting conditions was 143.46% (90% CI, 124.22-165.69). Nine subjects (28.1%) reported a total of 20 treatment-emergent adverse events (AEs). The most frequently reported AEs were gastrointestinal disorders (6 subjects [18.8%]) and central nervous system disorders (4 [12.5%]). Eight AEs considered possibly or probably related to sapropterin were reported by 4 subjects (12.5%); these were of mild severity and gastrointestinal in nature. No severe or serious AEs or discontinuations due to AEs occurred during the study. CONCLUSIONS: Administration of sapropterin as intact tablets and with a high-calorie, high-fat meal was associated with increased drug exposure. Oral administration of sapropterin 10 mg/kg as intact tablets with or without food was generally well tolerated.