The Bioequivalence and Effect of Food on the Pharmacokinetics of a Fixed-Dose Combination Tablet Containing Rosuvastatin and Ezetimibe in Healthy Japanese Subjects.

Certain patient populations are unable to achieve the recommended low-density lipoprotein cholesterol goals with statin monotherapy alone. Such patients may benefit from concomitant therapy with ezetimibe (EZE) 10 mg added on to a statin. To this end, fixed-dose combination (FDC) tablets containing EZE 10 mg and rosuvastatin (ROS) 2.5 mg (EZE/ROS2.5) and EZE 10 mg and ROS 5 mg (EZE/ROS5) have been developed for treatment of hypercholesterolemia. The purpose of the series of clinical studies reported herein was to evaluate the potential food effect (MK-0653H, protocol 836 (P836)) and the bioequivalence between FDC and co-administration of EZE and ROS in healthy Japanese subjects under fasted and fed conditions (MK-0653H, protocol 835 (P835) and MK-0653H, protocol 846 (P846), respectively). These studies show there is no clinically relevant food effect on EZE exposure following single oral administration of the FDC EZE/ROS5 in healthy Japanese subjects; however, ROS exposure was decreased in the fed state under conditions used to evaluate the maximum food effect. Following single oral administration of individual ROS tablets under the same conditions, the magnitude of decrease in ROS exposure was comparable to that seen with FDC, suggesting that the effect of food on ROS exposure was similar between the FDC tablet and co-administration of individual EZE and ROS tablets. The FDC EZE/ROS5 was generally well tolerated in healthy Japanese subjects under fasted and fed conditions.

Characterisation of the absorption, distribution, metabolism, excretion and mass balance of doravirine, a non-nucleoside reverse transcriptase inhibitor in humans.

Absorption, distribution, metabolism and elimination of doravirine (MK-1439), a novel non-nucleoside reverse transcriptase inhibitor, were investigated. Two clinical trials were conducted in healthy subjects: an oral single dose [14 C]doravirine (350 mg, ∼200 µCi) trial (n = 6) and an intravenous (IV) single-dose doravirine (100 µg) trial (n = 12). In vitro metabolism, protein binding, apparent permeability and P-glycoprotein (P-gp) transport studies were conducted to complement the clinical trials. Following oral [14 C]doravirine administration, all of the administered dose was recovered. The absorbed dose was eliminated primarily via metabolism. An oxidative metabolite (M9) was the predominant metabolite in excreta and was the primary circulating metabolite (12.9% of circulating radioactivity). Following IV administration, doravirine clearance and volume of distribution were 3.73 L/h (95% confidence intervals (CI) 3.09, 4.49) and 60.5 L (95% CI 53.7, 68.4), respectively. In vitro, doravirine is not highly bound to plasma proteins (unbound fraction 0.24) and has good passive permeability. The metabolite M9 was generated by cytochrome P450 3A (CYP3A)4/5-mediated oxidation. Doravirine was a P-gp substrate but P-gp efflux is not expected to play a significant role in limiting doravirine absorption or to be involved in the elimination of doravirine. In conclusion, doravirine is a low clearance drug, primarily eliminated by CYP3A-mediated metabolism.

The Effect of Food on Doravirine Bioavailability: Results from Two Pharmacokinetic Studies in Healthy Subjects.

BACKGROUND AND OBJECTIVE: Doravirine is a novel non-nucleoside reverse transcriptase inhibitor being developed for the treatment of HIV-1. In two open-label, single-dose, randomized, two-period, crossover trials, the bioavailability of doravirine administered alone or in a fixed-dose combination (FDC) was determined under fed and fasted conditions. METHODS: Doravirine 100 mg alone or with lamivudine and tenofovir disoproxil fumarate (each 300 mg) were administered to healthy subjects fasted or 30 min after a high-fat, high-calorie breakfast. Twenty-eight subjects, aged 26-55 years, enrolled (doravirine, n = 14; FDC, n = 14). The sequence of fed/fasted treatment was randomized (1:1). Pharmacokinetic data were analyzed as geometric mean ratios (GMRs) with 90% confidence intervals. RESULTS: Doravirine area under the plasma concentration-time curve (AUC) from time zero to infinity (fed/fasted GMRs: alone 1.16 [1.06-1.26]; FDC 1.10 [1.02-1.20]), AUC from time zero to the last measurement (GMRs: alone 1.18 [1.08-1.29]; FDC 1.10 [1.01-1.20]), and plasma concentration 24 h after administration (GMRs: alone 1.36 [1.19-1.55]; FDC 1.26 [1.13-1.41]) values increased in the fed versus fasted state when administered alone or as the FDC; the magnitude was not clinically meaningful. Doravirine maximum achieved concentration was similar after fed or fasted administration for both doravirine alone and FDC (GMRs: alone 1.03 [0.89-1.19]; FDC 0.95 [0.80-1.12]). The pharmacokinetics of tenofovir and lamivudine in the FDC were also slightly altered by administration with food; the changes were not clinically meaningful. CONCLUSIONS: All treatments were generally well tolerated. Food had no clinically meaningful effect on doravirine 100 mg alone or as part of an FDC.

Effect of gender and age on the relative bioavailability of doravirine: results of a Phase I trial in healthy subjects.

BACKGROUND: Doravirine is a potent, once-daily, non-nucleoside reverse transcriptase inhibitor with a distinct resistance profile in Phase III development for the treatment of HIV-1. As doravirine may be administered to women and the elderly, we investigated the effect of gender and age in doravirine pharmacokinetics. METHODS: In this Phase I, open-label, single-period, parallel-group investigation, doravirine 100 mg was administered to 36 healthy subjects in three groups: elderly men (n=12, 65-80 years), elderly women (n=12, 65-80 years) and young women (n=12, 18-50 years). Data for young men (n=6, 18-50 years) from a previous study were included as a comparator. Doravirine plasma pharmacokinetics and safety were assessed. RESULTS: No clinically meaningful effect on pharmacokinetics was observed in association with gender or age. Gender effects were assessed using combined data from elderly and young men versus elderly and young women because the datasets met predefined pooling criteria. The geometric mean ratios (GMRs; women/men [90% CIs]) of doravirine AUC0-∞, Cmax and C24h were 1.20 (1.03, 1.40), 1.42 (1.23, 1.64) and 1.02 (0.84, 1.24), respectively. Age effects were assessed separately in men and women because the datasets did not meet pooling criteria. The AUC0-∞, Cmax, and C24h GMRs (elderly/young) were 0.85 (0.67, 1.10), 0.92 (0.73, 1.16), 0.81 (0.59, 1.11), respectively for men and 0.97 (0.79, 1.19), 1.18 (0.98, 1.42), 0.94 (0.72, 1.21), respectively, for women. Doravirine was well-tolerated throughout the trial. CONCLUSIONS: Neither gender nor age affects the bioavailability of single-dose doravirine 100 mg in healthy subjects, thus supporting administration of doravirine 100 mg in elderly and adult women without dose adjustment.

The Absence of a Clinically Significant Effect of Food on the Single Dose Pharmacokinetics of Vorapaxar, a PAR-1 Antagonist, in Healthy Adult Subjects.

In this open-label, randomized, 2-period crossover study, 16 healthy subjects received a single oral 2.5-mg dose of vorapaxar in the fed (i.e., standardized high-fat breakfast) and fasted (i.e., an overnight fast) state with a 6-week washout. Plasma samples for vorapaxar assay were obtained pre-dose and up to 72 hours post-dose. Least squares (LS) geometric mean AUC0-72 hr and Cmax were analyzed by ANOVA. If 90% confidence intervals (CI) for the geometric mean ratios (GMRs; fed/fasted) of AUC0-72 hr and Cmax were within the 50-200% range, then food was deemed not to have a clinically important effect. The LS geometric mean (90% CI) AUC0-72 hr and Cmax of vorapaxar in the fasted state were 314 (284-348) ng hr/mL and 23.4 (20.7-26.4) ng/mL, respectively. The GMRs (fed/fasted) and 90% CIs for AUC0-72 hr and Cmax were 96.9 (92.2-102) and 79.1 (67.6-92.5), respectively. Vorapaxar was generally safe and well tolerated in the presence and absence of food. Concomitant food decreased the rate (i.e., 21% reduction in Cmax and 45-min delay in Tmax ) with no effect on the extent of vorapaxar absorption when administered as a single 2.5-mg dose. Thus, vorapaxar can be administered without regard to food.

Effect of telcagepant on spontaneous ischemia in cardiovascular patients in a randomized study.

OBJECTIVE: The primary purpose of the study was to explore the safety and tolerability of telcagepant in patients with stable coronary artery disease. BACKGROUND: Triptans are effective acute anti-migraine drugs whose vasoconstrictive effects limit their use in patients at risk for adverse cardiovascular events. Telcagepant, a calcitonin gene-related peptide receptor antagonist, is being developed for the acute treatment of migraine. Antagonism of calcitonin gene-related peptide, which does not appear to cause vasoconstriction, may allow for treatment of migraine in patients with coronary artery disease. METHODS: In this randomized, double-blind, placebo-controlled, crossover study, patients with documented stable coronary artery disease were assigned to 1 of 2 treatment sequences: telcagepant then placebo, or placebo then telcagepant. In each treatment period, patients received 2 doses of telcagepant 300-mg or placebo 2 hours apart. They remained in the research center for 24 hours after receiving the first dose of each period, during which time continuous 12-lead ambulatory electrocardiographic (Holter) monitoring was performed. RESULTS: Twenty-eight patients were enrolled; all patients completed the study and were included in all analyses. Telcagepant was generally well tolerated. No laboratory or serious adverse experiences were reported, and no patient discontinued due to an adverse experience. There were no consistent treatment-related changes in laboratory, vital signs or electrocardiogram safety parameters. Three patients (2 after receiving placebo and 1 after receiving telcagepant) experienced ST segment depression during the study; none of these patients reported chest pain. CONCLUSIONS: Two doses of 300-mg telcagepant, administered 2 hours apart, did not appear to exacerbate spontaneous ischemia and were generally well tolerated in a small cohort of patients with stable coronary artery disease. Results of this study support further evaluation of telcagepant in patients with stable coronary artery disease.

Treatment of infants and toddlers with cystic fibrosis-related pancreatic insufficiency and fat malabsorption with pancrelipase MT.

BACKGROUND: Pancreatic enzyme replacement therapy (PERT) improves nutritional status and growth in patients with cystic fibrosis (CF) with pancreatic insufficiency (PI). The current recommendation for infants and young children, who are not able to swallow the whole capsule, is to open the capsule and mix the beads in a spoon with some applesauce; however, the efficacy and safety data of this approach are currently lacking. The aim of this study was to assess the efficacy, palatability (ease of swallowing), and safety of 4 dose levels of pancrelipase microtablets (Pancrease MT) in infants and young children with CF-related PI. PATIENTS AND METHODS: This study was a phase II randomized, investigator-blinded, parallel-group pilot study in DNA-proven infants with CF and PI. The study design included a run-in period (days 1-5) and an experimental period (days 6-11). Pancrelipase microtablets (2-mm, enteric coated) were provided orally. Sixteen subjects, 6 to 30 months of age, were provided 500 U lipase/kg/meal for 5 days (baseline period). Subsequently, subjects were randomly assigned to 1 of 4 treatment groups (each n = 4), receiving 500, 1000, 1500, or 2000 U (Ph. EUR) of lipase/kg/meal, respectively, for 5 days (experimental period). The primary endpoint was medication efficacy assessed by the 72-hour fecal fat excretion, expressed as coefficient of fecal fat absorption (CFA), and 13C mixed triglyceride breath test. Secondary endpoints were safety and palatability. RESULTS: Overall compliance, defined as used study medication, was 89% to 99% for the entire study. None of the 4 dose regimens significantly influenced the CFA, relative to the baseline period (median range 83%-93%). During the run-in period the median cumulative % 13C was 11 (range -8 to 59). After randomization the median cumulative % 13C was 18 (range 14-23) in the 500-U, 14 (range -1 to 17) in the 1000-U, 10 (range 10-27) in the 1500-U, and 3 (range 1-49) in the 2000-U groups. Palatability was scored fair to good by the parents in each of the treatment groups. Gastrointestinal symptoms were reported in some patients, including common adverse events reported in clinical trials involving pancreatic enzyme therapy. No serious or other adverse events were reported. CONCLUSION: Treatment with Pancrease MT at a dosage of 500 U lipase/kg/meal resulted in a CFA of approximately 89% in pediatric subjects ages 6 to 30 months with PI resulting from CF. Pancrease MT doses were well tolerated and mean palatability was scored as fair to good. Present results do not indicate that a dosage higher than 500 U (Ph. EUR) lipase/kg/meal increases the coefficient of fat absorption in a cohort of infants 6 to 30 months of age.

PhRMA white paper on ADME pharmacogenomics.

Pharmacogenomic (PGx) research on the absorption, distribution, metabolism, and excretion (ADME) properties of drugs has begun to have impact for both drug development and utilization. To provide a cross-industry perspective on the utility of ADME PGx, the Pharmaceutical Research and Manufacturers of America (PhRMA) conducted a survey of major pharmaceutical companies on their PGx practices and applications during 2003-2005. This white paper summarizes and interprets the results of the survey, highlights the contributions and applications of PGx by industrial scientists as reflected by original research publications, and discusses changes in drug labels that improve drug utilization by inclusion of PGx information. In addition, the paper includes a brief review on the clinically relevant genetic variants of drug-metabolizing enzymes and transporters most relevant to the pharmaceutical industry.