Pharmacokinetics of indinavir combined with low-dose ritonavir in human immunodeficiency virus type 1-infected children.

So far, no pediatric doses for indinavir combined with ritonavir have been defined. This study evaluated the pharmacokinetics of 400 mg of indinavir/m(2) combined with 125 mg of ritonavir/m(2) every 12 h (q12h) in 14 human immunodeficiency virus type 1-infected children. The area under the concentration-time curve from 0 to 24 h and the minimum concentration of drug in serum for indinavir were similar to those for 800 mg of indinavir-100 mg of ritonavir q12h in adults, while the maximum concentration of drug in serum was slightly decreased, with geometric mean ratios (90% confidence intervals in parentheses) of 1.1 (0.87 to 1.3), 0.96 (0.60 to 1.5), and 0.80 (0.68 to 0.94), respectively.

An extended point-area deconvolution approach for assessing drug input rates.

PURPOSE: To describe an extended point-area deconvolution approach for evaluating drug input rates based on the application of piecewise cubic polynomial functions. METHODS: Both the nonimpulse response data and the impulse reference data were independently represented by the piecewise cubic polynomials to obtain interpolations, numerical integration, and reduced step size for the staircase input rates. A moving average algorithm was employed to compute the input rate estimates. The method was illustrated using data from preclinical and human studies. Simulations were used to examine the effects of data noise. RESULTS: In all cases examined, the piecewise cubic interpolation functions combined with the moving average algorithm yielded estimates that were reasonable and acceptable. Compared to the standard point-area approach based on the trapezoidal rule, the present method resulted in estimates that were closer to the expected values. CONCLUSIONS: The point-area deconvolution analysis is one of the preferred approaches in assessing pharmacokinetic and biopharmaceutic data when it is undesirable to assume the functional forms of the input processes. The present method provides improved performance and greater flexibility of this approach.

Pharmacokinetic profile and tolerability of indinavir-ritonavir combinations in healthy volunteers.

This was a randomized, double-blind, placebo-controlled parallel study in human immunodeficiency virus type 1 (HIV-1)-uninfected healthy subjects to investigate the pharmacokinetic interaction between indinavir (IDV) and ritonavir (RTV). Subjects were allocated to treatment groups of IDV given with RTV in the following milligram doses twice daily: 800 mg of IDV-100 mg of RTV (800-100 mg), 800-200, 800-400, and 400-400 mg, placebo of IDV with RTV doses of 100, 200, and 400 mg, and placebo of both IDV and RTV. Doses of both drugs were administered for 14 days with a low-fat meal and one dose on day 15 with a high-fat meal. Blood was obtained for drug concentration measurements on days 14 and 15. Seventy-three volunteers enrolled in the study: 29 men and 44 women. Fifty-three volunteers completed the study. When compared to standard historical data for 800 mg of IDV every 8 h (q8h), the IDV area under the concentration-time curve for 24 h (AUC(24)) of IDV-RTV regimens 400-400, 800-100, and 800-200 mg were at least 1.4, 2.3, and 3.3 times higher, respectively, regardless of meal. The concentrations at the end of the dosing interval were 10 to 25 times higher than that observed in the standard regimen of 800 mg of IDV q8h for IDV-RTV 800-100 and 800-200 mg regimens, respectively. RTV at 200 mg maximally enhanced the IDV profile. Improved tolerability was associated with IDV-RTV 800-100 mg versus IDV-RTV 800-200, 800-400, and 400-400 mg q12h. The advantages of IDV-RTV twice daily over 800 mg of IDV q8h include no food restrictions and twice-daily dosing. Also, the regimens achieve levels of IDV that may be helpful in suppressing strains of HIV-1 that have reduced susceptibility to IDV or other protease inhibitors.

Use of in vitro drug metabolism data to evaluate metabolic drug-drug interactions in man: the need for quantitative databases.

It has become widely accepted that metabolic drug-drug interactions can be forecast using in vitro cytochrome P450 (CYP) data. For any CYP form-inhibitor pair, the magnitude of the interaction will depend on the potency of the inhibitor (inhibition constant, Ki) the concentration of the inhibitor available for inhibition ([I]), the fraction of the substrate dose metabolized by CYP (fm), and the fraction of the CYP-dependent metabolism catalyzed by the inhibited CYP form (e.g., fm,CYP3A4). While progress is being made toward our understanding of the factors necessary for predictions of [I]/Ki in vivo, it is evident that there is a need for quantitative databases that contain in vitro (e.g., Ki, fm,CYP3A4) and in vivo pharmacokinetic/absorption-distribution-metabolism-excretion (PK/ADME) data (e.g., fm) for a large number of marketed drugs. Ultimately, such databases would allow one to integrate all of the data necessary for the prediction of drug-drug interactions and permit the rational evaluation of new drug entities.

The steady-state disposition of indinavir is not altered by the concomitant administration of clarithromycin.

STUDY OBJECTIVES: To evaluate the safety and potential pharmacokinetic interaction between indinavir and clarithromycin. STUDY METHODS: In a randomized, three-period, crossover fashion, 12 healthy adults received the following for 1 week: 800 mg oral indinavir sulfate every 8 hours with placebo, 500 mg oral clarithromycin every 12 hours with placebo, and indinavir sulfate with clarithromycin. Plasma indinavir, clarithromycin, and 14-hydroxyclarithromycin concentrations were determined after the last dose in each treatment period. RESULTS: Administration of indinavir sulfate with clarithromycin caused a statistically significant increase in four pharmacokinetic parameters: a 58% increase in plasma indinavir concentrations at 8 hours (P = .029), a 47% increase in values for clarithromycin area under the plasma concentration versus time curve from time zero to the last measured concentration [AUC(0-12h); P = .0002], and 49% and 48% decreases in 14-hydroxyclarithromycin AUC(0-12h) and maximum plasma concentration (Cmax) values, respectively (P = .0001 and P = .0001). These effects are not considered to be clinically significant in view of the insignificant effects on the values for indinavir area under the plasma concentration versus time curve from time zero to the last measured concentration [AUC(0-8h)] and Cmax, as well as the safety profile of clarithromycin. CONCLUSIONS: The combination of indinavir sulfate and clarithromycin is generally well tolerated and can be coadministered without dose adjustment.

Effect of MK-386, a novel inhibitor of type 1 5 alpha-reductase, alone and in combination with finasteride, on serum dihydrotestosterone concentrations in men.

Two isozymes (types 1 and 2) of 5 alpha-reductase (5 alpha R; EC 1.3.99.5), with differential tissue distribution, have been identified in humans. These enzymes catalyze the reduction of testosterone (T) to dihydrotestosterone (DHT). The contributions of each of these isozymes to serum and tissue concentrations of DHT remain to be fully defined. Finasteride, a selective inhibitor of type 2 5 alpha R, lowers circulating DHT levels by approximately 70% in men after treatment with 5 mg daily. MK-386 (4,7 beta-dimethyl-4-aza-5 alpha-cholestan-3-one) is a new selective inhibitor of type 1 5 alpha R. A single rising dose, alternating panel, trial in 16 healthy males (age range, 21-25 yr) studied the effect of 0.1-100 mg MK-386. DHT was maximally reduced by 20-30% relative to placebo at MK-386 doses of 10 mg or more, orally, by 24 h posttreatment (P < 0.01 vs. placebo). No consistent effect on T concentrations was evident. In a second trial, finasteride (5 mg) was given for 19 days to 10 healthy young men (age range, 24-47 yr); a 25-mg dose of MK-386 was added for 2 days of combination therapy after at least 10 days of finasteride treatment. Withdrawal of MK-386 was followed by 5-6 days of finasteride follow-up treatment. Finasteride alone reduced DHT, on the average, by 68.7% (SE = 3.4%). Addition of MK-386 suppressed DHT by 89.5% (SE = 1.4%) relative to baseline (P < 0.01 vs. effect of finasteride alone). Small increases in serum T were observed with finasteride alone and in combination with MK-386 (approximately 10% and 19%, respectively). These data are consistent with selective 5 alpha R type 1 inhibition in man by MK-386 and the prediction that types 1 and 2 5 alpha R account for all, or nearly all, of circulating DHT. Further clinical trials are needed to assess the therapeutic utility of type 1 5 alpha R inhibition as well as that of combined inhibition of types 1 and 2 5 alpha R.

Plasma concentrations and effect on testosterone metabolism after single doses of MK-0434, a steroid 5 alpha-reductase inhibitor, in healthy subjects.

A four-period, two-panel, single-rising-dose study (0.1-100 mg) was conducted in healthy males to investigate the pharmacodynamics, tolerability and pharmacokinetics of MK-0434, a steroid 5 alpha-reductase inhibitor. MK-0434 was associated with a significant reduction in dihydrotestosterone, which was maximal at 24 h and maintained through 48 h post treatment. The maximum reduction was approximately 50% and occurred at all doses above 5 mg (10, 25, 50 and 100 mg). MK-0434 appeared to have no effect on serum testosterone at these single doses. Rising single doses of MK-0434 were associated with an increase in Cmax and AUC but the changes were less than proportional to dose, most likely due to nonlinear absorption. MK-0434 given in single doses up to 100 mg was without significant adverse effects in healthy male volunteers. In summary, MK-0434 is a well-tolerated, potent, orally active 5 alpha-reductase inhibitor in man.

Finasteride, a steroid 5 alpha-reductase inhibitor, does not affect the oxidative metabolism of antipyrine.

A single-blind study was conducted to investigate the effect of multiple doses of finasteride, a 5 alpha-reductase inhibitor for the treatment of benign prostatic hyperplasia, on the single-dose pharmacokinetics of antipyrine. Twelve patients with benign prostatic hyperplasia received a total of four single oral doses of 18 mg/kg antipyrine before, during, and after treatment with 10 mg/day of finasteride for 28 days. Finasteride had no effect on antipyrine concentration profiles. There were also no changes in urinary excretion of three principal antipyrine metabolites. A slight increase in renal clearance of antipyrine was observed; however, this is not considered relevant because excretion of unchanged antipyrine represents a minor fraction of total elimination and is not directly related to oxidative metabolism. These results imply that significant interactions between finasteride and drugs metabolized by these cytochrome P-450 enzymes are unlikely.