Assessment of activity levels for CYP2D6*1, CYP2D6*2, and CYP2D6*41 genes by population pharmacokinetics of dextromethorphan.

The pharmacokinetics of dextromethorphan (DM) is markedly influenced by cytochrome P450 2D6 (CYP2D6) enzyme polymorphisms. The aim of this study was to quantify the effects of the CYP2D6*1, *2, and *41 variants on DM metabolism in vivo and to identify other sources of pharmacokinetic variability. Concentrations of DM and dextrorphan (DO) in plasma and urine were evaluated in 36 healthy Caucasian men. These volunteers participated in three clinical studies and received a single oral dose of 30 mg DM-HBr. Data were modeled simultaneously using the population pharmacokinetics NONMEM software. A five-compartment model adequately described the data. The activity levels of the alleles assessed differed significantly. The clearance attributable to an individual CYP2D6*1 copy was 2.5-fold higher as compared with CYP2D6*2 (5,010 vs. 2,020 l/h), whereas the metabolic activity of CYP2D6*41 was very low (85 l/h). Urinary pH was confirmed as a significant covariate for DM renal clearance. These results refine genotype-based predictions of pharmacokinetics for DM and presumably for other CYP2D6 substrates as well.

Pharmacokinetic/pharmacodynamic modeling of biomarker response to sunitinib in healthy volunteers.

A pharmacokinetic/pharmacodynamic (PK/PD) study of the tyrosine kinase inhibitor sunitinib was conducted in 12 healthy volunteers using blood pressure and circulating biomarker levels as PD markers. Blood pressure was measured, and plasma concentration-time courses of sunitinib, its major metabolite SU12662, vascular endothelial growth factors VEGF-A and VEGF-C, and soluble VEGF receptor-2 (sVEGFR-2) were studied in healthy subjects receiving 50 mg of sunitinib orally for 3-5 consecutive days. Using NONMEM, PK/PD models were established that predicted changes (expressed as multiples relative to baseline values) in systolic blood pressure, diastolic blood pressure, VEGF-A level, and sVEGFR-2 level, of 1.10, 1.18, 2.24, and 0.76, respectively, for a typical subject after 4 weeks of treatment with 50 mg/day. Simulated blood pressure-time courses compare excellently with published data in patients, whereas changes in circulating biomarkers were greater in patients than simulations suggest for healthy subjects. In conclusion, the tumor-independent pharmacological response to sunitinib could be described by PK/PD models, thereby facilitating model-based investigations with antiangiogenic drugs, using blood pressure and circulating proteins as biomarkers.

Plasma 4beta-hydroxycholesterol: an endogenous CYP3A metric?

We assessed the suitability of 4beta-hydroxycholesterol (4betaOH-C) as an endogenous cytochrome P450 3A (CYP3A) phenotyping metric. 4betaOH-C and its ratio to cholesterol (4betaOH-C/C) were determined in five cocktail phenotyping studies, with and without co-medication with a potential CYP3A inhibitor. These parameters were compared with established midazolam-based CYP3A metrics: clearance after intravenous (i.v.) administration (M-Cl) and apparent clearance after oral administration (M-Cl/F), reflecting hepatic and overall activity, respectively. In a common evaluation of periods without co-medication, there was a slight positive correlation of 4betaOH-C and 4betaOH-C/C with midazolam metrics: M-Cl (r = 0.239 and 0.348, respectively) and M-Cl/F (r = 0.267 and 0.353, respectively); P (one-sided) < 0.05. Co-medication with lopinavir/ritonavir caused a strong decrease in midazolam metrics and a mild decrease in cholesterol metrics. However, the intake of propiverine resulted in opposite trends for midazolam-based and cholesterol-based metrics. The information currently available does not justify the use of 4betaOH-C for estimation of basal CYP3A activity. Further studies to address the temporal variations in local CYP3A activity are needed to assess its role as a biomarker during CYP3A inhibition.

The clinical role of genetic polymorphisms in drug-metabolizing enzymes.

For most drug-metabolizing enzymes (DMEs), the functional consequences of genetic polymorphisms have been examined. Variants leading to reduced or increased enzymatic activity as compared to the wild-type alleles have been identified. This review tries to define potential fields in the therapy of major medical conditions where genotyping (or phenotyping) of genetically polymorphic DMEs might be beneficial for drug safety or therapeutic outcome. The possible application of genotyping is discussed for depression, cardiovascular diseases and thromboembolic disorders, gastric ulcer, malignant diseases and tuberculosis. Some drugs used for relief of these ailments are metabolized with participation of genetically polymorphic DMEs including CYP2D6, CYP2C9, CYP2C19, thiopurine-S-methyltransferase, dihydropyrimidine dehydrogenase, uridine diphosphate glucuronosyltransferase and N-acetyltransferase type 2. Current evidence suggests that taking genetically determined metabolic capacities of DMEs into account has the potential to improve individual risk/benefit relationship. However, more prospective studies with clinical endpoints are needed before the paradigm of 'personalized medicine' based on DME variants can be established.

Effect of propiverine on cytochrome P450 enzymes: a cocktail interaction study in healthy volunteers.

The present study was conducted to assess a possible in vivo effect of propiverine, an anticholinergic drug to treat urinary incontinence and related disorders, on the activity of intestinal CYP3A4 and of hepatic CYP3A4, CYP2C9, CYP2C19, and CYP1A2. The activity of the respective cytochromes P450 was measured using the following metrics of selective substrates given as a tailored low-dose phenotyping cocktail: intestinal availability of midazolam (2 mg orally), clearance of midazolam (1 mg i.v.), apparent clearance of tolbutamide (125 mg orally), urinary excretion of 4'-hydroxymephenytoin 0 to 8 h postdose (50 mg of mephenytoin orally), and the paraxanthine/caffeine plasma ratio 6 h postdose (150 mg of caffeine orally). These metrics were determined in 16 healthy young men at the end of 7 days of treatment with 15 mg of propiverine (test) or placebo (reference) twice daily. All phenotyping drugs were quantified by liquid chromatography-tandem mass spectrometry. Chronic propiverine treatment reduced hepatic and intestinal CYP3A4 activity slightly to 0.89-fold and 0.80-fold, respectively [90% confidence interval (CI) for test/reference ratios 0.85-0.93 and 0.72-0.89], with the combined effect resulting in a 1.46-fold increase in area under the curve of oral midazolam (90% CI 1.36-1.57). Propiverine had no relevant effect on CYP2C9, CYP2C19, and CYP1A2 (90% CI for test/reference ratios 0.93-1.00, 0.84-0.96, and 0.97-1.07, respectively). All study drugs were well tolerated. In conclusion, propiverine has a minor potential to cause drug-drug interactions.

Dermal absorption of permethrin following topical administration.

OBJECTIVE: Permethrin is an insecticide used in the treatment of lice and scabies infections. Although its efficacy and safety have been well documented, pharmacokinetic data are sparse. The objective of this study was to determine the systemic exposure of permethrin and the duration of residence in the human body following topical administration. METHODS: The study consisted of three parts. In six young healthy men (part 1), 50 ml of an ethanolic solution containing 215 mg permethrin (cis/trans: 25/75) was administered to the hair of the head. In another six young healthy men (part 2) and in six male or female scabies patients (part 3), 60 g of cream containing 3 g permethrin was administered to the skin of the whole body. Urine was collected up to 168 h post-dose. Urinary excretion of the main metabolite of permethrin, 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid, and its conjugates was measured using a gas chromatography/electron capture detection method. RESULTS: Pharmacokinetics were similar in all study parts. The time of maximal urinary excretion rate was 12.3, 20.0 and 14.6 h, terminal elimination half-life was 32.7, 28.8 and 37.8 h and urinary recovery of the metabolite reached 0.35, 0.47 and 0.52 M percent of the permethrin dose, respectively, in parts 1, 2 and 3 (means). The treatment was well tolerated. CONCLUSIONS: The extent of systemic exposure following external therapeutic administration of permethrin is very low compared with doses used for preclinical toxicity studies, and elimination is virtually complete after 1 week. These data provide the pharmacokinetic basis for the clinical safety of topical permethrin.

Pharmacokinetics of ibuprofen sodium dihydrate and gastrointestinal tolerability of short-term treatment with a novel, rapidly absorbed formulation.

OBJECTIVE: This paper describes four studies investigating the dissolution, plasma pharmacokinetics and safety of a novel, fast-acting ibuprofen formulation, ibuprofen sodium dihydrate. MATERIAL AND METHOD: Four separate studies investigated: the in vitro dissolution rates of ibuprofen sodium dihydrate (at pH 1.2, 3.5 and 7.2); the bioavailability of ibuprofen sodium dihydrate (in two pharmacokinetic studies; combined n = 38) compared with conventional ibuprofen, ibuprofen lysinate, ibuprofen arginate and ibuprofen liquagels (all 2 x 200 mg ibuprofen); and the gastroduodenal tolerance of ibuprofen sodium dihydrate and ibuprofen arginate (both 2 x 200 mg ibuprofen t.i.d.) in an endoscopy safety study, where endoscopy was performed at baseline and at the end of each treatment period using a five-point scale to assess the integrity of the gastric and duodenal mucosa. RESULTS: Ibuprofen sodium dihydrate dissolved significantly more rapidly at pH 1.2, 3.5 and 7.2 than conventional ibuprofen, ibuprofen lysinate and ibuprofen liquagels. Ibuprofen sodium dihydrate had similar C(max) to ibuprofen lysinate and ibuprofen liquagels and significantly higher Cmax than conventional ibuprofen (p = 0.002). The mean plasma concentration for ibuprofen sodium dihydrate was significantly higher than for conventional ibuprofen (p = 0.028) 10 minutes post-dose and the t(max) for ibuprofen sodium dihydrate was reached significantly earlier than for conventional ibuprofen (p = 0.018). All three formulations were bioequivalent according to the acceptable boundaries (90% confidence intervals). No statistically significant difference was observed between the ibuprofen formulations in terms of adverse events and specifically with respect to hemorrhagic scores; 41 (46.0%) adverse events (AEs) occurred after administration of ibuprofen sodium dihydrate, and 46 (52.9%) after ibuprofen arginate. One occurrence of an invasive ulcer was observed after administration of ibuprofen arginate. CONCLUSIONS: The new formulation of ibuprofen sodium dihydrate dissolves quickly in vitro, has the same extent of absorption as other fast-acting ibuprofen formulations, and is absorbed into plasma more rapidly than conventional ibuprofen. In addition, the present studies suggest that the tolerability and safety profile of ibuprofen sodium dihydrate is comparable to existing ibuprofen formulations.