Trimethoprim/sulfamethoxazole does not affect the steady-state disposition of indinavir.

This study evaluates the safety and potential pharmacokinetic interaction between indinavir and trimethoprim/sulfamethoxazole (TMP/SMZ). In a randomized, three-period crossover fashion, 12 healthy adults received 1 week of indinavir sulfate 400 mg orally every 6 hours with placebo, TMP 160 mg/SMZ 800 mg orally every 12 hours with placebo, and indinavir sulfate with TMP/SMZ. Plasma indinavir, SMZ, and TMP concentrations were determined after the last dose of each treatment period. Concomitant administration resulted in a 17% decrease in geometric mean trough plasma indinavir concentrations (p = 0.032), an 18% increase in geometric mean AUC0-12 h and Cmax TMP values (p = 0.031 and 0.030, respectively), and a 5% increase in geometric mean AUC0-12 h SMZ values (p = 0.039). None of these effects was considered clinically significant. The combination of indinavir sulfate and TMP/SMZ is generally well tolerated, with no clinically significant pharmacokinetic interaction being noted.

Determination of an in vivo metabolite of a human immunodeficiency virus protease-inhibitor in human plasma by high-performance liquid chromatography with tandem mass spectrometry.

A method for the determination of a metabolic of the human immunodeficiency virus protease inhibitor indinavir, in human plasma is described. Isolation of the analyte and the internal standard from plasma was achieved via liquid-liquid extraction with a mixture of isopropanol-chloroform (5:95, v/v). The analytes were chromatographed under reversed-phase conditions on a Waters Symmetry C, column. A Sciex API III+ tandem mass spectrometer equipped with a heated nebulizer was used as a detector and was operated in the positive ion mode. Multiple reaction monitoring using the precursor-->production combinations of m/z, 523.4-->273.4 and 512.4-->345.2 was used to quantify analyte and internal standard, respectively. The method was validated in the concentration range of 5-500 ng/ml plasma with adequate assay precision and accuracy. The assay was used to analyze samples collected during drug interaction studies of indinavir.

Determination of L-735 524, an human immunodeficiency virus protease inhibitor, in human plasma and urine via high-performance liquid chromatography with column switching.

A method for the determination of an HIV protease inhibitor, L-735 524, in human plasma and urine is described. Isolation of the analyte and the internal standard from the matrices was achieved via multiple liquid-liquid extractions with methyl tert.-butyl ether. The analyte lacks significant UV absorption at wavelengths greater than 220 nm, hence a column switching system using a cyano and C18 column was used to further purify the extracts prior to UV detection at 210 nm. The assay has been found to be linear and has been validated over the concentration range of 5 to 500 ng/ml, when 1-ml aliquots of plasma or urine were extracted. The assay has been utilized to support human pharmacokinetic studies.

Determination of MK-507, a novel topically effective carbonic anhydrase inhibitor, and its de-ethylated metabolite in human whole blood, plasma, and urine by high-performance liquid chromatography.

Sensitive methods for the determination of a novel topically effective carbonic anhydrase inhibitor (CAI) I, MK-507, and its de-ethylated metabolite II, in human whole blood, plasma and urine were developed. These methods were based on liquid-liquid extraction of I and II from biological matrices, back extraction into acid, and analysis by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection (252 nm). The assays were fully validated in the concentration range of 5 to 500 ng/ml, and the limit of quantification (LOQ) for I and II, defined as the lowest concentration on the standard curve for which precision (coefficient of variation, C.V.) is < 10%, was 5 ng/ml in whole blood, plasma, and urine. These methods were applied for the analyses of biological fluid samples from a variety of clinical pharmacokinetic studies. In addition, a method in whole blood based on column-switching HPLC with UV detection and with an LOQ of 50 ng/ml was also developed. The switching valve was used to eliminate interferences from late eluting peaks extracted from whole blood. The details of these assays, together with some representative data from a human study, are presented.

Single-dose pharmacokinetics of indinavir and the effect of food.

Indinavir sulfate is a human immunodeficiency virus type 1 (HIV-1) protease inhibitor indicated for treatment of HIV infection and AIDS in adults. The purpose of this report is to summarize single-dose studies which characterized the pharmacokinetics of the drug and the effect of food in healthy volunteers. Indinavir concentrations in plasma and urine were obtained by high-pressure liquid chromatography and UV detection assay methods. The results indicate that indinavir was rapidly absorbed in the fasting state, with the time to the maximum concentration in plasma occurring at approximately 0.8 h for all doses studied. Over the 40- to 1,000-mg dose range studied, concentrations in plasma and urinary excretion of unchanged drug increased greater than dose proportionally. The nonlinear pharmacokinetics were attributed to the dose-dependent oxidative metabolism of first-pass metabolism as well as to metabolism in the systemic circulation. Renal clearance slightly exceeded the glomerular filtration rate, suggesting a net tubular secretion component. At high concentrations in plasma, tubular secretion appeared to be lowered because there was a trend for a decreased renal clearance. Administration of 400 mg of indinavir sulfate following a high-fat breakfast resulted in a blunted and decreased absorption (areas under the concentration-time curves [AUCs], 6.86 microM.h in the fasted state versus 1.54 microM.h in the fed state; n = 10). However, two types of low-fat meals were found to have no significant effect on the absorption of 800 mg of indinavir sulfate (AUCs, 23.15 microM.h in the fasted state versus 22.71 and 21.36 microM.h, respectively, in the fed state; n = 11). Immediately following dosing, the concentrations of indinavir in urine often exceeded its intrinsic solubility. To reduce the risk of nephrolithiasis, it is recommended that indinavir sulfate be administered with water.