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SummaryBackground Few pharmacokinetic (PK) and pharmacodynamic (PD) data exist for COX-2 selective inhibitors in children. We wished to characterize the PKPD of parecoxib and its active metabolite, valdecoxib, in this population. Methods Children (n = 59) were randomized to parecoxib 0.25 mg·kg−1, 1 mg·kg−1, and 2 mg·kg−1 during tonsillectomy ± adenoidectomy. Samples (4–6 per child) were obtained from indwelling cannula over 6 h. A second group of inpatient children (n = 15) given 1 mg·kg−1 contributed PK data from 6 to 24 h. Pain scores and rescue medication for the first group were recorded postoperatively for up to 24 h. PK data were pooled with those (10 samples/24 h) from a published study of children (n = 38) who underwent surgery. A three-compartment parent and one-compartment metabolite model with first-order elimination was used to describe data using nonlinear mixed effects models. An EMAX model described the relationship between dose and rescue morphine equivalents during recovery. Results Parecoxib PK parameter estimates were CLPARECOXIB 19.1 L·h−1·70 kg−1, V1PARECOXIB 4.2 L·70 kg−1, Q2PARECOXIB 6.29 L·h−1·70 kg−1, V2PARECOXIB 130 L·70 kg−1, Q3PARECOXIB 6.02 L·h−1·70 kg−1, and V3PARECOXIB 2.03 L·70 kg−1. We assumed all parecoxib was metabolized to valdecoxib with CLVALDECOXIB 9.53 L·h−1·70 kg−1 and VVALDECOXIB 51 L·70 kg−1. There was no maturation of clearance over the age span studied. There were no differences in pain scores between groups on waking, discharge, 12 h, or 24 h. There were no differences in analgesia consumption over 24 h between groups for tramadol, fentanyl, and morphine rescue use. Fentanyl and morphine consumption, expressed as morphine equivalents (0.13 mg·kg−1) in the 0.25 mg·kg−1 group, was greater than that observed in the 1 or 2 mg·kg−1 groups (0.095 mg·kg−1) in PACU. Conclusions Parecoxib 0.9 mg·kg−1 in a 2-year-old, 0.75 mg·kg−1 in a 7-year-old, and 0.65 mg·kg−1 in a 12-year-old child achieves dose equivalence of 40 mg in a standard 70 kg person. Clearance maturation may occur in infants younger than the current cohort. Parecoxib doses above 1 mg·kg−1 add no additional analgesia.

Aims The aim of the present study was to investigate the safety, tolerability and pharmacokinetics of coadministered azithromycin (AZI) and piperaquine (PQ) for treating malaria in pregnant Papua New Guinean women. Methods Thirty pregnant women (median age 22 years; 16-32 weeks' gestation) were given three daily doses of 1 g AZI plus 960 mg PQ tetraphosphate with detailed monitoring/blood sampling over 42 days. Plasma AZI and PQ were assayed using liquid chromatography-mass spectrometry and high-performance liquid chromatography, respectively. Pharmacokinetic analysis was by population-based compartmental models. Results The treatment was well tolerated. The median (interquartile range) increase in the rate-corrected electrocardiographic QT interval 4 h postdose [12 (6-26) ms(0) (.5) ] was similar to that found in previous studies of AZI given in pregnancy with other partner drugs. Six women with asymptomatic malaria cleared their parasitaemias within 72 h. Two apararasitaemic women developed late uncomplicated Plasmodium falciparum infections on Days 42 and 83. Compared with previous pregnancy studies, the area under the concentration-time curve (AUC0-∞ ) for PQ [38818 (24354-52299) μg h l(-1) ] was similar to published values but there was a 52% increase in relative bioavailability with each dose. The AUC0-∞ for AZI [46799 (43526-49462) μg h l(-1) ] was at least as high as reported for higher-dose regimens, suggesting saturable absorption and/or concentration-dependent tissue uptake and clearance from the central compartment. Conclusions AZI-PQ appears to be well tolerated and safe in pregnancy. Based on the present/other data, total AZI doses higher than 3 g for the treatment and prevention of malaria may be unnecessary in pregnant women, while clearance of parasitaemia could improve the relative bioavailability of PQ.