This work provides a perspective on the qualification and verification of physiologically based pharmacokinetic (PBPK) platforms/models intended for regulatory submission based on the collective experience of the Simcyp Consortium members. Examples of regulatory submission of PBPK analyses across various intended applications are presented and discussed. European Medicines Agency (EMA) and US Food and Drug Administration (FDA) recent draft guidelines regarding PBPK analyses and reporting are encouraging, and to advance the use and acceptability of PBPK analyses, more clarity and flexibility are warranted.

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ObjectiveEvaluate the human abuse potential, pharmacokinetics, pharmacodynamics, and safety of NKTR-181, a novel mu-opioid agonist molecule, relative to oxycodone.DesignThis randomized, single-center, double-blind, active- and placebo-controlled five-period crossover study enrolled healthy, adult, non–physically dependent recreational opioid users.SettingInpatient clinical research site.SubjectsForty-two randomized subjects (73.8% male, 81% white, mean age = 25 years).MethodsThe primary objective was to evaluate single orally administered 100, 200, and 400 mg NKTR-181 doses in solution compared with 40 mg oxycodone and placebo solutions using the Drug Liking visual analog scale. Secondary measures included the Drug Effects Questionnaire, Addiction Research Center Inventory/Morphine Benzedrine Group Subscale, Price Value Assessment Questionnaire, Global Assessment of Overall Drug Liking, and Take Drug Again Assessment. Central nervous system mu-opioid effects were assessed using pupillometry. The study included qualifying and treatment phases. Subjects received each of the five treatments using a crossover design.ResultsNKTR-181 at all dose levels had significantly lower Drug Liking Emax than oxycodone (P < 0.0001). Drug Liking scores for oxycodone increased rapidly within 15 minutes and peaked at approximately one hour postdose, whereas Drug Liking (and most secondary abuse potential measures) for all doses of NKTR-181 were comparable with placebo for at least the first hour. Only the 400 mg Drug Liking scores were minimally differentiated vs placebo from one and a half to four hours, but remained significantly lower than oxycodone (P < 0.003). NKTR-181 treatment-related adverse effects were mild and occurred at a lower rate compared with oxycodone.ConclusionsNKTR-181 demonstrated delayed onset of CNS effects and significantly lower abuse potential scores compared with oxycodone in recreational opioid users.

To determine whether stavudine (2',3'-didehydro-3'-deoxythymidine) is actively transported in vivo across the placenta and to determine the extent of its transfer, stavudine was administered as an intravenous bolus to four near-term macaques (Macaca nemestrina) (5 mg/kg of body weight via the femoral vein) or to their fetuses (10 mg/kg via the carorid artery) at gestational age 134 +/- 5 days, with the administrations about 1 week apart. Antipyrine (a passive diffusion marker) was always coadministered (20 mg/kg) with stavudine. Samples of maternal and fetal plasma and amniotic fluid were collected at frequent intervals up to 240 min after the dose. In a separate experiment, three animals received stavudine for 30 h at a low rate of infusion (22 micrograms/min/kg via the femoral vein) to the dam or at a 10-fold-higher rate of infusion (220 micrograms/min/kg), separated by at least one week, in order to determine if the transplacental transfer of stavudine is saturable. Antipyrine (41.7 micrograms/min/kg) was coinfused with stavudine. Samples of maternal and fetal plasma and amniotic fluid were collected at regular intervals for up to 30 h. The concentrations of stavudine and antipyrine were determined by high-performance liquid chromatography. The transplacental maternal-fetal drug clearances were compared by the paired Student t test. The clearance associated with maternal-fetal transfer of the drug (CLdf) (0.54 +/- 0.08 ml/min/kg) was not significantly different (P > 0.05) from the clearance associated with fetal-maternal transfer of the drug, CLfd (0.66 +/- 0.11 ml/min/kg). Also, CLdf was not significantly different (P > 0.05) from CLfd when normalized with respect to the corresponding transplacental clearance of antipyrine (0.23 +/- 0.04 versus 0.36 +/- 0.25). The ratios of the steady-state plasma stavudine concentration in the fetus to that in the dam were 0.77 +/- 0.06 at the low stavudine infusion rate and 0.81 +/- 0.09 at the high stavudine infusion rate. The obtained data indicate that transfer of stavudine across the placenta is passive and constant over the dose range studied.