Clinical Pharmacology in Drug Development

We conducted an open-label, single-dose, randomized, crossover study in healthy adults to assess the impact of food on the bioavailability of 60 mg methylphenidate extended-release oral suspension (MEROS; Quillivant XR™)-a long-acting stimulant for the treatment of attention deficit hyperactivity disorder-by comparing the pharmacokinetic parameters under fed and fasting conditions. When MEROS 60 mg was administered under fed conditions compared with fasting conditions, the exposure of methylphenidate (d enantiomer) was higher, with a mean area under the plasma concentration-vs-time curve (AUC)0-t of 160...

OM3-CA (omega-3-carboxylic acids) is a complex mixture of omega-3 carboxylic acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which is approved in the United States for the treatment of hypertriglyceridemia. As part of its clinical development in Japan, we performed a phase 1 study to investigate the safety, tolerability, and pharmacokinetics after single and multiple doses of OM3-CA in healthy male Japanese subjects. Eighteen Japanese subjects were allocated to receive 2 or 4 g/day OM3-CA, or placebo (n = 6 per group)...

This study investigated the effects of ingested meal types on the pharmacokinetics of elvitegravir (EVG), cobicistat (COBI), emtricitabine (FTC), tenofovir alafenamide (TAF), and tenofovir (TFV) following a single administration of the single-tablet regimen (STR) of EVG/COBI/FTC/TAF (150/150/200/10 mg) in Japanese HIV-negative healthy subjects (n = 12). In this open-label, randomized, 3-way crossover study, the bioequivalence of the EVG/COBI/FTC/TAF STR following ingestion of a nutritional protein-rich drink with a reference treatment of taking a standard breakfast was evaluated...

Open-label single- and double-blind repeat-dose studies in healthy female volunteers were conducted to investigate the pharmacokinetics (PK) and safety/tolerability of epelsiban total daily doses ranging from 600 to 900 mg. In 1 study (n = 12), epelsiban was dosed at 300 or 450 mg twice daily (every 12 hours) for a single day. In the repeat-dose double-blind study, epelsiban and placebo were administered to 31 subjects as 200 mg 3 times daily, 300 mg 3 times daily (TID), or 450 mg twice daily (BID) for 14 days...

Extended-release (ER) methylphenidate (MPH) is a first-line treatment for attention-deficit/hyperactivity disorder. A methylphenidate extended-release orally disintegrating tablet (MPH XR-ODT) has recently been developed. This was a randomized, open-label, 3-period, 3-treatment study comparing the bioavailability and absorption of 2 MPH XR-ODT formulations with an MPH ER reference medication. Here we report the 2 treatments comparing the commercial MPH XR-ODT formulation and reference medication. Following a ≥10-hour fast, 42 healthy adults received 60 mg of reference medication or MPH XR-ODT (2 × 30 mg)...

Extended-release methylphenidate is a first-line treatment for attention-deficit/hyperactivity disorder. A methylphenidate extended-release orally disintegrating tablet (MPH XR-ODT) has recently been developed. Here we report an open-label, randomized, 2-period, 2-treatment crossover study to determine the effect of food on the bioavailability of a single 60-mg dose of MPH XR-ODT in healthy adults. Blood samples were collected predose through 36 hours postdose. Maximum plasma concentration (Cmax ), time to maximum plasma concentration (Tmax ), terminal elimination half-life (T1/2 ), overall systemic exposure (AUClast and AUCinf ), and partial areas under the concentration curve (AUC0-3 , AUC3-7 , and AUC7-12 ) were calculated...

This first-in-human dose-ascending study investigated pharmacokinetics, safety, and tolerability of pibrentasvir following single and multiple doses in healthy volunteers. Additionally, the effects of food and ritonavir on pibrentasvir were assessed in a crossover study design. The starting dose of pibrentasvir was selected based on the no-observed-adverse-effect-level exposure from preclinical studies. Dose escalations of subsequent cohorts were dependent on reviews of the safety, tolerability, and pharmacokinetic data from previous dose cohorts...

The first aim of the present study was to evaluate the bioavailability of ibuprofen dispersed in a novel soft chewable formulation compared with a traditional ibuprofen tablet; its second was to map the quality of taste masking and patient product satisfaction. In a phase 1, single-center, open-label, randomized, crossover study, healthy subjects received a soft-chew formulation or a hard tablet (reference), both containing 100 mg ibuprofen. Serial blood samples were collected over 24 hours to assess ibuprofen bioavailability...

Palbociclib free base capsule is a weak base drug with highly pH-dependent solubility. In vitro and in vivo studies evaluated the impact of acid-reducing agents on exposure of palbociclib and determined whether the impact, if any, can be mitigated by food. A drug-drug interaction study (study 1) was conducted first under fasted conditions and showed that coadministration of multiple doses of the proton-pump inhibitor rabeprazole substantially reduced palbociclib mean area under the concentration-time curve from time 0 to infinity and maximum observed plasma concentration by 62% and 80%, respectively...

A new once-daily formulation of raltegravir, an integrase strand transfer inhibitor indicated in combination with other antiretroviral drugs for the treatment of human immunodeficiency virus-1 infection, is under development. Single-dose and steady-state pharmacokinetics of 1200 mg for 2 formulations of raltegravir were characterized in 2 open-label phase 1 studies in healthy male and female subjects aged 18 to 55 years. The new raltegravir 600-mg formulation had a higher relative bioavailability compared with the 400-mg tablets...

Daprodustat (GSK1278863) is a prolyl hydroxylase inhibitor in phase 3 clinical studies for the treatment of anemia associated with chronic kidney disease. This study was conducted to evaluate the effect of daprodustat on cardiac repolarization and enrolled 55 healthy adult male (29) and female (26) subjects who received single-dose 75 and 500 mg daprodustat, 400 mg moxifloxacin, and placebo. Mean placebo-corrected change from baseline QT interval for daprodustat showed no statistically significant increase...

This study characterized the pharmacokinetics, safety, and tolerability of retosiban in healthy, nonpregnant Japanese women prior to the enrollment of Japanese women in preterm labor in phase 3 trials. This study had 2 cohorts. Cohort 1 was a double-blind, sponsor-open, randomized study in Japanese women. Cohort 2 was an open-label study in white women to compare the pharmacokinetics with those of Japanese women. Retosiban was administered as a 6 mg/h infusion for 24 hours, followed by a 12 mg/h infusion over the next 24 hours; each infusion was preceded by a 6 mg loading dose administered over 5 minutes...

Migraine, a common neurovascular brain disorder, represents a severe and widespread health problem; along with medication-induced (medication-overuse) headache, it is the third-leading cause of disability worldwide. Currently, its therapeutic management remains unsatisfactory for several reasons; up to 40% of migraineurs are eligible for prophylactic treatment, but there are issues of efficacy, safety, and adherence. In recent years the evidence on the role of calcitonin gene-related peptide (CGRP) in migraine pathophysiology has been consolidated, so new and promising treatments for migraine pain and its possible prevention have been developed...

Vorapaxar is a first-in-class antagonist of the protease-activated receptor-1, the primary thrombin receptor on human platelets, which mediates the downstream effects of thrombin in hemostasis and thrombosis. Prasugrel is a platelet inhibitor that acts as a P2Y12 receptor antagonist through an active metabolite, R-138727. This study investigated the interaction of these 2 platelet antagonists when coadministered. This was a randomized, open-label, multiple-dose study in 54 healthy volunteers consisting of a fixed-sequence crossover and a parallel group design...

This study evaluated whether deferiprone, an oral iron chelator, acts to prolong the QT interval. Fifty healthy volunteers received single doses of each of the following: therapeutic dose of deferiprone (33 mg/kg), supratherapeutic dose (50 mg/kg), placebo, or moxifloxacin, a positive control known to significantly prolong QT interval. Following each dose, subjects underwent cardiac monitoring, pharmacokinetics assessments, and safety assessments. Based on the QT interval obtained using the Fridericia correction for heart rate (QTcF), the upper bound of the 1-sided 95% confidence interval of the mean difference between deferiprone and placebo was <10 milliseconds (the threshold of concern defined by authorities) at all time points for both doses: maximum difference of 3...

No abstract text is available yet for this article.

This study was designed to investigate the pharmacokinetics of an innovative film-coated warfarin sodium tablet and to compare it with the marketed sugar-coated warfarin sodium tablet in humans. A single-dose, open-label, randomized, two-way crossover study was performed in 24 healthy Chinese male volunteers. They were administered 2.5 mg of innovative film-coated warfarin sodium tablets or the marketed sugar-coated warfarin sodium tablets. Blood samples were collected at different time points after dosing for investigation of the pharmacokinetics of warfarin in human plasma...

No abstract text is available yet for this article.

No abstract text is available yet for this article.

The study aimed to compare the pharmacokinetics of 2 pemetrexed formulations (Pemgem, Dr. Reddy's Laboratories w.r.t; Alimta, Eli Lilly) in adult chemonaive subjects with adenocarcinoma stage III/IV non-small cell lung cancer. All patients received 500 mg/m(2) pemetrexed (Alimta or Pemgem) as a 10-minute infusion on day 1 of a 21-day cycle. Plasma pemetrexed concentrations were determined on day 1 of cycle 1. Area under the concentration-time curve (AUC0-inf ) and the maximum plasma concentration (Cmax ) were estimated using noncompartment analysis and compared between the 2 arms...