The accuracy of physiologically based pharmacokinetic (PBPK) model prediction in children, especially those younger than 2 years old, has not been systematically evaluated. The aim of this study was ...to characterize the pediatric predictive performance of the PBPK approach for 10 drugs extensively metabolized by CYP1A2 (theophylline), CYP2C8 (desloratidine, montelukast), CYP2C9 (diclofenac), CYP2C19 (esomeprazole, lansoprazole), CYP2D6 (tramadol), and CYP3A4 (itraconazole, ondansetron, sufentanil). Model performance in children was evaluated by comparing simulated plasma concentration–time profiles with observed clinical results for each drug and age group. PBPK models reasonably predicted the pharmacokinetics of desloratadine, diclofenac, itraconazole, lansoprazole, montelukast, ondansetron, sufentanil, theophylline, and tramadol across all age groups. Collectively, 58 out of 67 predictions were within 2‐fold and 43 out of 67 predictions within 1.5‐fold of observed values. Developed PBPK models can reasonably predict exposure in children age 1 month and older for an array of predominantly CYP metabolized drugs.
The objective of this study was to investigate the efficacy and safety of adjunctive lanicemine (NMDA channel blocker) in the treatment of major depressive disorder (MDD) over 12 weeks. This phase ...IIb, randomized, parallel-arm, double-blind, placebo-controlled study was conducted at 49 centers in four countries between December 2011 and August 2013 in 302 patients aged 18-70 years, meeting criteria for single episode or recurrent MDD and with a history of inadequate treatment response. Patients were required to be taking an allowed antidepressant for at least four weeks prior to screening. Patients were randomized equally to receive 15 double-blind intravenous infusions of adjunctive lanicemine 50 mg, lanicemine 100 mg, or saline over a 12-week course, in addition to ongoing antidepressant. The primary efficacy end point was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to week 6. Secondary efficacy outcome variables included change in MADRS score from baseline to week 12, response and remission rates, and changes in Clinical Global Impression scale, Quick Inventory of Depressive Symptomology Self-Report score, and Sheehan Disability Scale score. Of 302 randomized patients, 240 (79.5%) completed treatment. Although lanicemine was generally well tolerated, neither dose was superior to placebo in reducing depressive symptoms on the primary end point or any secondary measures. There was no significant difference between lanicemine and placebo treatment on any outcome measures related to MDD. Post hoc analyses were performed to explore the possible effects of trial design and patient characteristics in accounting for the contrasting results with a previously reported trial.
Aims
Naloxegol, a polyethylene glycol conjugated derivative of the opioid antagonist naloxone, is in clinical development for treatment of opioid‐induced constipation (OIC).
The aim of the study was ...to develop a population pharmacokinetic model describing the concentration vs. time profile of orally administered naloxegol, and determine the impact of pre‐specified demographic and clinical factors and concomitant medication on population estimates of apparent clearance (CL/F) and apparent central compartment volume of distribution (Vc/F).
Methods
Analysis included 12 844 naloxegol plasma concentrations obtained from 1247 healthy subjects, patients with non‐OIC and patients with OIC in 14 phase 1, 2b and 3 clinical studies. Pharmacokinetic analysis used the non‐linear mixed effects modelling program. Goodness of fit plots and posterior predictive checks were conducted to confirm concordance with observed data.
Results
The final model was a two compartment disposition model with dual absorptions, comprising one first order absorption (ka1 4.56 h−1) and one more complex absorption with a transit compartment (ktr 2.78 h−1). Mean (SE) parameter estimates for CL/F and Vc/F, the parameters assessed for covariate effects, were 115 (3.41) l h–1 and 160 (27.4) l, respectively. Inter‐individual variability was 48% and 51%, respectively. Phase of study, gender, race, concomitant strong or moderate CYP3A4 inhibitors, strong CYP3A4 inducers, P‐glycoprotein inhibitors or inducers, naloxegol formulation, baseline creatinine clearance and baseline opioid dose had a significant effect on at least one pharmacokinetic parameter. Simulations indicated concomitant strong CYP3A4 inhibitors or inducers had relevant effects on naloxegol exposure.
Conclusions
Administration of strong CYP3A4 inhibitors or inducers had a clinically relevant influence on naloxegol pharmacokinetics.
A population model describing quetiapine pharmacokinetics (PK) in Western and Chinese patients following oral administration of immediate‐release (IR) and extended‐release (XR) formulations was ...developed using plasma concentrations in 127 patients from 5 studies with quetiapine IR and/or XR in Western patients and 1 study with quetiapine XR in Chinese patients. A 1‐compartmental model with first‐order absorption and first‐order elimination adequately described the quetiapine PK. The typical apparent volume of distribution and elimination rate constant of quetiapine were 574 L and 0.12 h−1, respectively. The estimated population absorption rate constants were 1.46 and 0.10 h−1 for quetiapine IR and XR, respectively. Covariate analysis revealed that race was not a significant covariate influencing the PK of quetiapine. Simulation conducted with the final quetiapine population PK model predicted that the administration of a 200‐mg twice‐daily dose of quetiapine IR in Chinese patients would achieve a steady‐state AUC (AUCss) ± standard deviation of 3087 ± 1480 ng · h/mL, which is in close agreement with the reported value (3538 ± 1728 ng · h/mL). The model also predicted that once‐daily administration of 300 mg quetiapine IR or XR would achieve similar exposure in terms of AUCss in Chinese patients.
The objectives of the present study were to evaluate safety and tolerability as well as the effects of multiple doses of lanicemine on the pharmacokinetics of a CYP3A substrate, midazolam. A total of ...46 healthy volunteers were enrolled in the open‐label, fixed‐sequence, nonrandomized study. All volunteers received an oral dose of 5 mg of midazolam alone or after 6 days of 150 mg daily intravenous infusion of lanicemine. Lanicemine reached a plasma Cmax of 1.51 μg/mL after 150 mg daily dosing to steady state. The geometric mean CL, Vss, and t1/2 of lanicemine were 8.1 L/h, 122.0 L, and 10.4 hours, respectively. The geometric least‐squares mean ratios and 90% confidence intervals for midazolam AUC0–∞, and Cmax were within the 80% to 125% limits when lanicemine plus midazolam treatment was compared with midazolam alone, demonstrating that daily dosing with 150 mg of lanicemine for 6 days had no effect on CYP3A activity. Comprehensive physiologically based pharmacokinetic modeling using in vitro and in silico findings also indicated lanicemine would have little impact on the pharmacokinetics of CYP3A substrate, such as midazolam. In addition, lanicemine and midazolam administered alone or in combination were generally safe and well tolerated.
The high rate of attrition during drug development and its associated high research and development (R&D) cost have put pressure on pharmaceutical companies to ensure that candidate drugs going to ...clinical testing have the appropriate quality such that the biological hypothesis could be evaluated. To help achieve this ambition, drug metabolism and pharmacokinetic (DMPK) science and increasing investment have been deployed earlier in the R&D process. To gain maximum return on investment, it is essential that DMPK concepts are both appropriately integrated into the compound design process and that compound selection is focused on accurate prediction of likely outcomes in patients. This article describes key principles that underpin the contribution of DMPK science for small-molecule research based on 15 years of discovery support in a major pharmaceutical company. It does not aim to describe the breadth and depth of DMPK science, but more the practical application for decision making in real-world situations.
Abstract
1. (1S)-1-phenyl-2-(pyridin-2-yl)ethanamine (lanicemine; AZD6765) is a low-trapping N-methyl-d-aspartate (NMDA) channel blocker that has been studied as an adjunctive treatment in major ...depressive disorder. The metabolism and disposition of lanicemine was determined in six healthy male subjects after a single intravenous infusion dose of 150 mg 14C-lanicemine.
2. Blood, urine and feces were collected from all subjects. The ratios of Cmax and AUC(0-∞) of lanicemine to plasma total radioactivity were 84 and 66%, respectively, indicating that lanicemine was the major circulating component with T1/2 at 16 h. The plasma clearance of lanicemine was 8.3 L/h, revealing that lanicemine is a low-clearance compound. The mean recovery of radioactivity from urine was 93.8% of radioactive dose.
3. In urine samples, 10 metabolites of lanicemine were identified. Among which, an O-glucuronide conjugate (M1) was the most abundant metabolite (∼11% of the dose in excreta). In plasma, the circulatory metabolites were identified as a para-hydroxylated metabolite (M1), an O-glucuronide (M2), an N-carbamoyl glucuronide (M3) and an N-acetylated metabolite (M6). The average amount of each of metabolite was less than 4% of total radioactivity detected in plasma or urine.
4. In conclusion, lanicemine is a low-clearance compound. The unchanged drug and metabolites are predominantly eliminated via urinary excretion.
Naloxegol is approved for the treatment of opioid‐induced constipation (OIC) in adults with chronic noncancer pain. Population exposure‐response models were developed using data from a phase II study ...comprising 185 adults with OIC. The weekly probability of response defined as having ≥3/week spontaneous bowel movements (SBMs) and ≥1 SBM/week increase over baseline was characterized by a longitudinal mixed‐effects logistic regression dose‐response model, and the probability of time to discontinuation was modeled with a Weibull distribution function. The predicted probability of SBM in a given week increased with increasing naloxegol dose. The model predicted that 12.5, 25, and 37.5 mg doses would produce median response rates of 40%, 50%, and 60%, and dropout rates of 13.3%, 16.7%, and 23.3%, respectively. The large overlap of predicted difference of the response rate between placebo and the 25 or 37.5 mg doses suggested little utility of using a 37.5 mg dose in phase III studies.
4-({4-(2-hydroxy-ethyl)-methyl-carbamoyl-phenyl}-quinolin-8-yl-methylene)-1-thiazol-4-ylmethyl-piperidinium (compound I) is a selective agonist of δ-opioid receptor developed for the treatment of ...depressive and anxiety disorders. The in vitro biotransformation studies using rat, dog, and human hepatocytes showed that the metabolites detected in human hepatocytes were also found in either rat or dog hepatocytes. M1 (N-dealkylation), M2 (N-demethylation), and M4 (carboxylic acid metabolite) were major phase I metabolites observed in all three species. Human CYP3A4/5 isoenzymes were identified to be the primary enzymes responsible for the formation of M1 and M2 in human liver microsomes. After single oral administration of ¹⁴Ccompound I, the major elimination route for (¹⁴Ccompound I and its metabolites in rat was through feces with 92.9% recovery. The results from the bile duct-cannulated study revealed that a minimum of 51% of administered dose was absorbed in rats. The pharmacokinetic analysis using unlabeled parent drug showed that compound I was rapidly absorbed and exhibited a mean apparent terminal half-life of approximately 2.7 h. A total of 15 metabolites of compound I were detected and profiled in rat urine, bile, and feces. In rat bile, compound I accounted for <1.5% of the excreted dose, suggesting that compound I underwent extensive metabolism before elimination. The structures of metabolites were elucidated by high-resolution tandem mass spectrometry. M1, M4, and M6 were the most abundant metabolites observed in rat bile. Only a low level of parent ¹⁴Ccompound I was observed in rat plasma.
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