Bruce K. Birmingham

Rosuvastatin pharmacokinetics and pharmacogenetics in white and Asian subjects residing in the same environment

Systemic exposure to rosuvastatin had been observed to be approximately 2‐fold higher in Japanese subjects living in Japan compared with white subjects in Western Europe or the United States. The organic anion transporting polypeptide 1B1 contributes to the hepatic uptake of rosuvastatin. Polymorphisms in the SLCO1B1 gene can lead to reduced transport function in vitro (T521>C). This study was conducted to determine whether the pharmacokinetic differences between Japanese and white subjects extended to other Asian ethnic groups and to determine whether polymorphisms in the SLCO1B1 gene contribute to any pharmacokinetic differences observed.

The effect of gemfibrozil on the pharmacokinetics of rosuvastatin

Coadministration of statins and gemfibrozil is associated with an increased risk for myopathy, which may be due in part to a pharmacokinetic interaction. Therefore the effect of gemfibrozil on rosuvastatin pharmacokinetics was assessed in healthy volunteers. Rosuvastatin has been shown to be a substrate for the human hepatic uptake transporter organic anion transporter 2 (OATP2). Inhibition of this transporter could increase plasma concentrations of rosuvastatin. The effect of gemfibrozil on rosuvastatin uptake by cells expressing OATP2 was also examined.

Evaluation of the effect of dapagliflozin on cardiac repolarization: a thorough QT/QTc study.

IntroductionDapagliflozin is a first-in-class sodium-glucose transporter 2 (SGLT2) inhibitor under investigation for the treatment of type 2 diabetes mellitus. A thorough QTc study was conducted, according to International Conference on Harmonization E14 guidelines, to characterize the effect of dapagliflozin on cardiac repolarization.MethodsThe present study was a double-blind, four-period, placebo-controlled crossover study at a single-center inpatient clinical pharmacology unit. The study enrolled 50 healthy men who were randomized to receive sequences of single doses of dapagliflozin 150 mg, dapagliflozin 20 mg, moxifloxacin 400 mg, and placebo. The sequences were randomized based on the Williams design for a cross-over study to reduce the “carryover” effects from drug-to-drug even with sufficient washout periods. Digital 12-lead electrocardiograms were recorded at nine time points over 24 hours in each period. QT intervals were corrected for heart rate using a study-specific correction factor (QTcX) and Fridericia’s formula.ResultsFor dapagliflozin, the upper bound of the one-sided 95% confidence interval (CI) for time-matched, placebo-subtracted, baseline adjusted QTc intervals (ΔΔQTc) was <10 ms. ΔΔQTc was independent of dapagliflozin concentrations. No QTc thresholds >450 ms or QTc increases >30 ms were observed. Moxifloxacin increased the mean QTcX interval by 7.7 ms (lower bound 90% CI, 6.2 ms) over 1–4 hours after dosing, confirming assay sensitivity.ConclusionDapagliflozin, at supratherapeutic doses, does not have a clinically significant effect on the QT interval in healthy subjects.

Population pharmacokinetics of rosuvastatin: implications of renal impairment, race, and dyslipidaemia.

ABSTRACT Objectives: To build the structural model of pharmacokinetics for rosuvastatin and evaluate the impact of demographic characteristics including renal function on its pharmacokinetic parameters. Methods: A population pharmacokinetic analysis of rosuvastatin in healthy volunteers, subjects with dyslipidaemia, and renal failure patients was performed using non-linear mixed-effects modelling and a two-compartment pharmacokinetic model with simultaneous first- and zero-order absorption. Demographic covariates, dyslipidaemic state and renal function were evaluated for their impact on pharmacokinetic parameters by step-wise additions or deletions using the likelihood ratio test. Results: Typical pharmacokinetic parameters were estimated for a healthy white male subject. For example, apparent oral clearance (CL/F ) was estimated to be 257 L/h. Age, smoking status, weight, body surface area, and lean body mass had no significant effect on rosuvastatin pharmacokinetics. The model predicted that CL/F for subjects with creatinine clearance (CLCR ) of 30 mL/min (moderate renal impairment) and of 50 mL/min (mild renal impairment) was 17% and 9.7% lower, respectively, relative to subjects with CLCR of 94 mL/min, the data set median value. CL/F was reduced by 71.1% and 43.7% in subjects with dyslipidaemia and in Asian subjects, respectively. Conclusions: Reduction of CL/F of rosuvastatin is not considered clinically significant for patients with mild-to-moderate renal impairment. Rosuvastatin CL/F was reduced in subjects with dyslipidaemia, but it is important to realise that the safety/efficacy profile of rosuvastatin has been well established in this population. However, the potential for increased exposure in Asian subjects should be considered when initiating rosuvastatin treatment or increasing dose in this population.

Population pharmacokinetics of rosuvastatin in normal subjects and subjects with dyslipidemia

To conduct a population pharmacokinetic (PK) analysis assessing the effects of renal function and other covariates on rosuvastatin (RO) pharmacokinetics. Methods: A total of 10,078 RO plasma values collected from 16 clinical trials after single/multiple oral dosing of 5 to 80 mg RO to 945 volunteers, renal‐impaired subjects, or dyslipidemic subjects (DS) were used. A structural PK model was built using data from 10 phase I studies. Demographic covariates, creatinine clearance (CLCR), and RO dose were evaluated. Results: Structural PK model was a two‐compartment model with linear elimination and simultaneous first‐ and zero‐order absorption. Final model parameters (typical values) are: CL/F (257 L/hr), VC/F (899 L), V2/F (1380 L), Q2/F (67.9 L/hr), Ka (1.14 hr−1), D2 (4.48 hr), and F2(0.857). Age, smoking status, body weight, body surface area, and lean body mass had no effect on any PK parameters. CL/F was not significantly changed in subjects with mild/moderate renal impairment. CL/F was decreased in Japanese living in Japan (56% of Caucasians) and in DS (29% of volunteers). VC/F increased with increasing IBW slightly or in DS (153% of volunteers). Compared to Caucasians, Japanese exhibited lower V2/F (72%) and Ka (42%) and Black had lower Ka (5%) and D2 (69%). Females had a lower D2 (77% of males). Conclusions: Mild or moderate renal impairment did not alter RO PK. Ethnicity and subject status are 2 factors influencing systemic exposure to RO.

Population pharmacokinetics of esomeprazole in adult patients with gastroesophageal reflux disease

To establish a population pharmacokinetic (PK) model of esomeprazole (ESO), a proton‐pump inhibitor, in 36 adult patients with gastroesophageal reflex disease (GERD) symptoms following an oral administration of 40 mg ESO (AstraZeneca study SH‐QBE‐0008).

Population Pharmacokinetic Analysis of Zolmitriptan and Its Metabolite in Adults and Adolescents to Support Dose Selection in Children With Migraine

Zolmitriptan is a serotonin (5‐HT) 1B/1D receptor agonist effective for the treatment of migraine. This analysis aimed to develop a population pharmacokinetic (PK) model for zolmitriptan and its active metabolite in adults and adolescents and provide appropriate dosing regimens to be used in clinical trials for children 6–11 years old. The data from a single‐dose clinical study of 5.0‐mg zolmitriptan nasal spray (ZNS) conducted in adult and adolescent patients with migraine between migraine attacks was applied. Similar plasma concentration profiles of zolmitriptan and its metabolite, 183C91, were observed in adults and adolescents. A 1‐compartment model with first‐order absorption and first‐order elimination reasonably described the zolmitriptan PK. With a portion of elimination of zolmitriptan being treated as the conversion from zolmitriptan to 183C91, the disposition of 183C91 was described by a 1‐compartment model with first‐order elimination. The estimated typical apparent volume of distribution and clearance of zolmitriptan were 136 L and 121 L/h, respectively, with 56.5% and 42.6% between‐subject variability, respectively. Based on the simulation results with the final population PK model, a body weight–based dosing scheme of 5.0 and 2.5 mg ZNS in children greater than and less than 50 kg is recommended to achieve exposures similar to those of the adult and adolescent population administered 5.0 mg ZNS. The recommended doses for children to achieve exposure similar to that observed in adults given 2.5 mg ZNS are 2.5 mg (≥50 kg) and 1.0 mg (15–50 kg). These dosing regimens could be used in future clinical trials.

An Open‐Label, Randomized Bioavailability Study of Alternative Methods of Oral Administration of Naloxegol in Healthy Subjects

Naloxegol is a peripherally acting μ‐opioid receptor antagonist approved as an orally administered tablet for the treatment of opioid‐induced constipation. Patients with swallowing difficulties may benefit from alternative approaches to the oral administration of the whole‐tablet formulation of naloxegol. This open‐label, randomized, 4‐period, 4‐treatment, crossover, single‐dose study (NCT02446171) evaluated the pharmacokinetic (PK) characteristics of crushed naloxegol 25‐mg tablets (suspended in water) administered orally or by nasogastric tube and a naloxegol solution compared with the commercially available 25‐mg tablet formulation in healthy volunteers. The PK profiles for the crushed tablet, whether administered orally or by nasogastric tube, and the 25‐mg oral solution were similar to that of the 25‐mg tablet administered orally. Compared with naloxegol commercial tablets, the relative bioavailability of naloxegol using 3 alternative methods of administration was approximately 100%. For each pairwise treatment comparison of the 3 alternative methods with the approved whole tablet, the geometric least‐squares mean ratio ranges were 94.37%–100.04%, 94.83%–100.44%, and 97.05%–102.05% for area under the curve (AUC), AUC0–t, and maximum plasma concentration, respectively, and their 90% confidence intervals were entirely within the predefined 80% to 125% bioequivalence limits. Naloxegol was well tolerated when administered in both liquid and solid form.

Population pharmacokinetic model of omeprazole following single oral doses in pediatric subjects

To examine the effect of developmental changes on omeprazole (OME) pharmacokinetics (PK) in pediatric subjects.