Aim Large interindividual variability in morphine pharmacokinetics could contribute to variability in morphine analgesia and adverse events. Methods Influence of weight, genetic polymorphisms, race and sex on morphine clearance and metabolite formation from 220 children undergoing outpatient adenotonsillectomy was studied. A nonlinear mixed effects model was developed in NONMEM to describe morphine and morphine glucuronide pharmacokinetics. Results Children with ABCC3 −211C>T polymorphism C/C genotype had significantly higher levels of morphine-6-glucuronide and morphine-3-glucuronide formation (~40%) than C/T+T/T genotypes (p < 0.05). In this extended cohort similar to our earlier report, OCT1 homozygous genotypes (n = 13, OCT1*2–*5/*2–*5) had lower morphine clearance (14%; p = 0.06), and in addition complementing lower metabolite formation (~39%) was observed. ABCB1 3435C>T TT genotype children had lower levels of morphine-3-glucuronide formation though no effect was observed on morphine and morphine-6-glucuronide pharmacokinetics. Conclusion Our data suggest that besides bodyweight, OCT1 and ABCC3 genotypes play a significant role in the pharmacokinetics of intravenous morphine and its metabolites in children.

BackgroundCOX-2 inhibitors can be effective for acute migraine, but none is supplied in a rapidly absorbed, ready-to-use oral liquid formulation. DFN-15, a novel oral liquid formulation of celecoxib, is being developed for the acute treatment of migraine with or without aura. Clinical studies with this formulation are ongoing.ObjectivesThe objectives of the present study were to compare the bioavailability of DFN-15 with that of the commercial formulation of celecoxib 400-mg oral capsules (Celebrex®) and to determine the dose proportionality of DFN-15 in healthy fasted volunteers.MethodsThis single-dose randomized crossover study in 16 healthy fasted volunteers evaluated the pharmacokinetics and relative bioavailability of DFN-15 at doses of 120, 180, and 240 mg against the commercial formulation of celecoxib 400-mg oral capsules and determined the dose proportionality of DFN-15.ResultsThe maximum observed plasma concentrations (C max) of celecoxib after the administration of DFN-15 120, 180, and 240 mg (1062–1933 ng/ml) were higher than for the 400-mg oral capsules (611 ng/ml). The median time to peak concentration (T max) was within 1 h for DFN-15 and 2.5 h for the oral capsules. The pharmacokinetics of DFN-15 were dose proportional from 120 to 240 mg. Partial area under the plasma concentration–time curves (AUCs) from 15 min to 2 h for DFN-15 120 mg were at least threefold higher than for the oral capsules, and the relative bioavailability of DFN-15 was approximately 140% that of the oral capsules. DFN-15 was well tolerated, with no new or unexpected adverse events.ConclusionsBased on a faster rate of absorption and increased bioavailability, DFN-15 is being evaluated as an abortive medication for acute treatment in patients with migraine.

BackgroundMeasuring fetal drug concentrations is extremely difficult in humans. We conducted a study in pregnant sheep to simultaneously describe maternal and fetal concentrations of propofol, a common intravenous anesthetic agent used in humans. Compared to inhalational anesthesia, propofol supplemented anesthesia lowered the dose of desflurane required to provide adequate uterine relaxation during open fetal surgery. This resulted in better intraoperative fetal cardiac outcome. This study describes maternal and fetal propofol pharmacokinetics (PK) using a chronically instrumented maternal-fetal sheep model.MethodsFetal and maternal blood samples were simultaneously collected from eight mid-gestational pregnant ewes during general anesthesia with propofol, remifentanil and desflurane. Nonlinear mixed-effects modeling was performed by using NONMEM software. Total body weight, gestational age and hemodynamic parameters were tested in the covariate analysis. The final model was validated by bootstrapping and visual predictive check.ResultsA total of 160 propofol samples were collected. A 2-compartment maternal PK model with a third fetal compartment appropriately described the data. Mean population parameter estimates for maternal propofol clearance and central volume of distribution were 4.17 L/min and 37.7 L, respectively, in a typical ewe with a median heart rate of 135 beats/min. Increase in maternal heart rate significantly correlated with increase in propofol clearance. The estimated population maternal-fetal inter-compartment clearance was 0.0138 L/min and the volume of distribution of propofol in the fetus was 0.144 L. Fetal propofol clearance was found to be almost negligible compared to maternal clearance and could not be robustly estimated.ConclusionsFor the first time, a maternal-fetal PK model of propofol in pregnant ewes was successfully developed. This study narrows the gap in our knowledge in maternal-fetal PK model in human. Our study confirms that maternal heart rate has an important influence on the pharmacokinetics of propofol during pregnancy. Much lower propofol concentration in the fetus compared to maternal concentrations explain limited placental transfer in in-vivo paired model, and less direct fetal cardiac depression we observed earlier with propofol supplemented inhalational anesthesia compared to higher dose inhalational anesthesia in humans and sheep.

Veliparib (ABT-888) is a novel oral poly-ADP-ribose polymerase (PARP) inhibitor that is being developed for the treatment of hematologic malignancies and solid tumors. Although the pharmacokinetics of veliparib has been studied in combination with cytotoxic agents, limited information exists regarding the pharmacokinetics of chronically-dosed, single-agent veliparib, in patients with either BRCA 1/2–mutated cancer or PARP sensitive tumors. The objectives of the current analysis were to characterize the population pharmacokinetics of veliparib and its primary, active metabolite, M8, and to evaluate the relationship between veliparib and M8 concentrations and poly-ADP-ribose (PAR) level observed in peripheral blood mononuclear cells (PBMC). Seventy-one subjects contributed with veliparib plasma concentrations, M8 plasma concentrations, and PAR levels in PBMC. Veliparib and M8 concentrations were modeled simultaneously using a population PK approach. A two-compartment model with delayed first-order absorption and the elimination parameterized as renal (CLR/F) and non-renal clearance (CLNR/F) adequately described veliparib pharmacokinetics. The pharmacokinetics of the M8 metabolite was described with a two-compartment model. Creatinine clearance and lean body mass were identified as significant predictors of veliparib CLR/F and central volume of distribution, respectively. For a typical subject (LBM, 48 kg; CLCR, 95 mL/min), total clearance (CLR/F +CLNR/F), central and peripheral volume of distribution for veliparib were estimated as 17.3 L/h, 98.7 L and 48.3 L, respectively. At least 50% inhibition of PAR levels in PBMCs was observed at dose levels ranging from 50 to 500 mg.