Pharmacokinetics of nifedipine slow-release during sustained tocolysis.

OBJECTIVE: The pharmacokinetics of nifedipine as a tocolytic agent has not been studied in great detail in pregnant women and has instead focused on immediate release tablets and gastrointestinal therapeutic system (GITS) tablets. The aim of this study was to determine nifedipine slow-release half-life and distribution volume in pregnant women and to compare these with pharmacokinetic parameters of nifedipine in non-pregnant subjects described in the literature. MATERIALS: This is a study parallel to a trial studying women with threatened preterm labor between 26 + 0 and 32 + 2 weeks after initial tocolysis and a completed course of corticosteroids, who were randomly allocated to maintenance nifedipine (slow-release tablets 20 mg 4 times daily) or placebo. Exclusion criteria for the pharmacokinetic study were contra-indications for nifedipine, impaired liver function, and concomitant intake of inhibitors or inducers of the cytochrome P450 3A4 isoenzyme. Blood samples for measuring nifedipine plasma concentrations were drawn at t = 0, t = 12 hours, t = 24 hours, t = 48 hours, t = 72 hours, t = 7 days, and t = 9 days. METHODS: Pharmacokinetic parameters were estimated using iterative two-stage Bayesian population pharmacokinetic analysis by MWPharm© software. The study was designed to establish a correlation between body weight and nifedipine plasma level. RESULTS: The pharmacokinetic parameters of nifedipine slow-release tablets were determined from the data of 8 pregnant women. Nifedipine slow-release had a half-life of 2 - 5 hours, a mean distribution volume of 6.2 ± 1.9 L/kg (calculated while using a fixed biological availability of 0.45 taken from the literature due to lack of intravenous data in this population) compared to a half-life of 6 - 11 hours, and a distribution volume of 1.2 - 1.3 L/kg described in non-pregnant subjects in the literature. None of the women delivered during study medication. Study medication was continued for the duration of the pharmacokinetic study (9 days) in all women. A correlation between nifedipine plasma levels and maternal body weight was not demonstrated. This may have been caused by lack of power. CONCLUSION: Pregnant subjects in this study, using nifedipine slow-release tablets, showed a larger volume of distribution and a shorter elimination half-life than for non-pregnant subjects as published in the literature.

Recognition of impaired atomoxetine metabolism because of low CYP2D6 activity.

Ten out of 100 children treated for attention deficit hyperactivity disorder with standard doses of atomoxetine were selected by a neurologist for cytochrome P450 2D6 and cytochrome P450 2C19 genotyping, based on late response (>9 weeks) and adverse effects (gastrointestinal problems, sleeping disorders, malaise, inactivity, and mood instabilities). After genotyping, eight children were confirmed to have compromised cytochrome P450 2D6 activity because of at least one nonfunctional or less functional allele. Cytochrome P450 C19 is a minor pathway in atomoxetine metabolism and therefore of less importance. Tailored therapeutic advice was given to the neurologist. Four children with compromised cytochrome P450 2D6 activity responded better after decreasing their atomoxetine dose. The other four ceased treatment because of initial adverse effects. These cases indicate that compromised atomoxetine metabolism can be recognized, based on adverse effects and late response to atomoxetine. Physicians should be aware of the typical pattern of adverse effects and late response in atomoxetine treatment, possibly indicating compromised cytochrome P450 2D6 activity. Cytochrome P450 2D6 genotyping before atomoxetine treatment may be beneficial in preventing overdosing or early cessation. Further research is needed to establish the cost versus benefit ratio of prospective cytochrome P450 2D6 genotyping in atomoxetine treatment.