Pharmacokinetics of Indinavir and Ritonavir Administered at 667 and 100 Milligrams, Respectively, Every 12 Hours Compared with Indinavir Administered at 800 Milligrams Every 8 Hours in Human Immunodeficiency Virus-Infected Patients

Human immunodeficiency virus (HIV) patients on nucleoside or nucleotide reverse transcriptase inhibitors with HIV RNA at <1,000 copies/ml were randomized in an open-label study to administration of combined indinavir/ritonavir (IDV/RTV) at 667/100 mg every 12 h (q12h) or IDV alone at 800 mg q8h to determine the regimens' pharmacokinetics. On day 14, plasma IDV and RTV levels were determined over 24 h. Noncompartmental pharmacokinetics (minimum concentration of drug in serum [C(min)], area under the concentration-time curve from 0 to 24 h [AUC(0-24)], and maximum concentration of drug in serum [C(max)]) were expressed as geometric mean values with 90% confidence intervals (CI). The primary hypothesis was that the lower bound of the protocol-specified 90% CI for the geometric mean C(min) ratio of the combination compared to IDV alone regimen would be ≥2. Twenty-seven patients were enrolled, and 24 (15 male; average age, 42 years) completed the study. The C(min), AUC(0-24), and C(max) for IDV/RTV compared to IDV alone were 1,511 versus 250 nM, 119,557 versus 77,034 nM · h, and 10,428 versus 10,407 nM, respectively. Corresponding relationships for IDV/RTV compared to IDV alone were a 6.0-fold increase in C(min) (90% CI, 4.0, 9.3), an increase in AUC(0-24) (1.5-fold, 90% CI, 1.2, 2.0), and no increase in C(max). Adverse events were similar and generally mild, with no cases of nephrolithiasis. The geometric mean ratio of IDV C(min) for IDV/RTV compared to IDV was at least 2 by a lower bound of the 90% CI, satisfying the primary hypothesis. The C(max) was not increased, suggesting an IDV/RTV 667/100-mg toxicity profile may be similar to that of unboosted IDV

Single- and Multiple-Dose Pharmacokinetics of Caspofungin in Healthy Men

Caspofungin, a glucan synthesis inhibitor, is being developed as a parenteral antifungal agent. The pharmacokinetics of caspofungin following 1-h intravenous infusions in healthy men was investigated in four phase I studies. In an alternating two-panel (six men each), rising-single-dose study, plasma drug concentrations increased proportionally with the dose following infusions of 5 to 100 mg. The β-phase half-life was 9 to 10 h. The plasma drug clearance rate averaged 10 to 12 ml/min. Renal clearance of unchanged drug was a minor pathway of elimination (∼2% of the dose). Multiple-dose pharmacokinetics were investigated in a 2-week, serial-panel (5 or 6 men per panel) study of doses of 15, 35, and 70 mg administered daily; a 3-week, single-panel (10 men) study of a dose of 70 mg administered daily; and a parallel panel study (8 men) of a dose of 50 mg administered daily with or without a 70-mg loading dose on day 1. Moderate accumulation was observed with daily dosing. The degree of drug accumulation and the time to steady state were somewhat dose dependent. Accumulation averaged 24% at 15 mg daily and ∼50% at 50 and 70 mg daily. Mean plasma drug concentrations were maintained above 1.0 μg/ml, a target selected to exceed the MIC at which 90% of the isolates of the most clinically relevant species of Candida were inhibited, throughout therapy with daily treatments of 70 or 50 mg plus the loading dose, while they fell below the target for the first 2 days of a daily treatment of 50 mg without the loading dose. Caspofungin infused intravenously as a single dose or as multiple doses was generally well tolerated. In conclusion, the pharmacokinetics of caspofungin supports the clinical evaluation of once-daily dosing regimens for efficacy against fungal infections

Indinavir and rifabutin drug interactions in healthy volunteers.

Two studies examined the pharmacokinetics of indinavir and rifabutin when coadministered in healthy subjects. Rifabutin, which induces the expression of cytochrome P450 (CYP) 3A, and indinavir, which inhibits that enzyme system, are frequently coadministered in patients infected with HIV. The second study was undertaken to determine if altering the dose of rifabutin coadministered with indinavir would minimize the drug interaction observed in the first study. Two studies, each with a three-period crossover design, were performed. In study 1, standard doses of rifabutin and indinavir (300 mg of rifabutin qd and 800 mg indinavir q8h) were administered as monotherapy (with placebo to the other drug) or in combination to 10 volunteers for 10 days. In study 2, 150 mg qd of rifabutin together with 800 mg q8h of indinavir, 300 mg qd of rifabutin alone, or 800 mg q8h of indinavir alone was administered to 14 volunteers for 10 days. In study 1, the geometric mean ratio (GMR) (90% confidence interval [CI]) of the AUC((0-8h)) of indinavir, coadministered with rifabutin 300 mg qd compared to indinavir alone (with rifabutin placebo), was 0.66 (0.56, 0.77), while that of the AUC((0-24h)) of rifabutin, coadministered with indinavir compared to rifabutin alone (with indinavir placebo), was 2.73 (1.99, 3.77). In study 2, the GMR (90% CI) of the AUC((0-8h)) of indinavir, coadministered with rifabutin 150 mg qd compared to indinavir alone, was 0.68 (0.60, 0.76), while that of the AUC((0-24h)) of rifabutin, when rifabutin 150 mg qd was coadministered with indinavir compared to rifabutin 300 mg qd alone, was 1.54 (1.33, 1.79). For both studies 1 and 2, indinavir and rifabutin administered alone or in combination were generally well tolerated. No clinical or laboratory adverse experience was serious. These data demonstrate the important pharmacokinetic interactions between indinavir and rifabutin when they are coadministered. Indeed, these observations formed the basis for the subsequent ACTG 365 study that explored dose adjustments for these agents in combination regimens to preserve the sustained antiviral activity of indinavir in the absence of adverse events as a result of elevated circulating levels of rifabutin

Potential for Interactions between Caspofungin and Nelfinavir or Rifampin

The potential for interactions between caspofungin and nelfinavir or rifampin was evaluated in two parallel-panel studies. In study A, healthy subjects received a 14-day course of caspofungin alone (50 mg administered intravenously [IV] once daily) (n = 10) or with nelfinavir (1,250 mg administered orally twice daily) (n = 9) or rifampin (600 mg administered orally once daily) (n = 10). In study B, 14 subjects received a 28-day course of rifampin (600 mg administered orally once daily), with caspofungin (50 mg administered IV once daily) coadministered on the last 14 days, and 12 subjects received a 14-day course of caspofungin alone (50 mg administered IV once daily). The coadministration/administration alone geometric mean ratio for the caspofungin area under the time-concentration profile calculated for the 24-h period following dosing [AUC(0-24)] was as follows (values in parentheses are 90% confidence intervals [CIs]): 1.08 (0.93-1.26) for nelfinavir, 1.12 (0.97-1.30) for rifampin (study A), and 1.01 (0.91-1.11) for rifampin (study B). The shape of the caspofungin plasma profile was altered by rifampin, resulting in a 14 to 31% reduction in the trough concentration at 24 h after dosing (C(24h)), consistent with a net induction effect at steady state. Both the AUC and the C(24h) were elevated in the initial days of rifampin coadministration in study A (61 and 170% elevations, respectively, on day 1) but not in study B, consistent with transient net inhibition prior to full induction. The coadministration/administration alone geometric mean ratio for the rifampin AUC(0-24) on day 14 was 1.07 (90% CI, 0.83-1.38). Nelfinavir does not meaningfully alter caspofungin pharmacokinetics. Rifampin both inhibits and induces caspofungin disposition, resulting in a reduced C(24h) at steady state. An increase in the caspofungin dose to 70 mg, administered daily, should be considered when the drug is coadministered with rifampin

Disposition of Caspofungin: Role of Distribution in Determining Pharmacokinetics in Plasma

The disposition of caspofungin, a parenteral antifungal drug, was investigated. Following a single, 1-h, intravenous infusion of 70 mg (200 μCi) of [(3)H]caspofungin to healthy men, plasma, urine, and feces were collected over 27 days in study A (n = 6) and plasma was collected over 26 weeks in study B (n = 7). Supportive data were obtained from a single-dose [(3)H]caspofungin tissue distribution study in rats (n = 3 animals/time point). Over 27 days in humans, 75.4% of radioactivity was recovered in urine (40.7%) and feces (34.4%). A long terminal phase (t(1/2) = 14.6 days) characterized much of the plasma drug profile of radioactivity, which remained quantifiable to 22.3 weeks. Mass balance calculations indicated that radioactivity in tissues peaked at 1.5 to 2 days at ∼92% of the dose, and the rate of radioactivity excretion peaked at 6 to 7 days. Metabolism and excretion of caspofungin were very slow processes, and very little excretion or biotransformation occurred in the first 24 to 30 h postdose. Most of the area under the concentration-time curve of caspofungin was accounted for during this period, consistent with distribution-controlled clearance. The apparent distribution volume during this period indicated that this distribution process is uptake into tissue cells. Radioactivity was widely distributed in rats, with the highest concentrations in liver, kidney, lung, and spleen. Liver exhibited an extended uptake phase, peaking at 24 h with 35% of total dose in liver. The plasma profile of caspofungin is determined primarily by the rate of distribution of caspofungin from plasma into tissues

Model-Based Decision Making in Early Clinical Development: Minimizing the Impact of a Blood Pressure Adverse Event

We describe how modeling and simulation guided program decisions following a randomized placebo-controlled single-rising oral dose first-in-man trial of compound A where an undesired transient blood pressure (BP) elevation occurred in fasted healthy young adult males. We proposed a lumped-parameter pharmacokinetic–pharmacodynamic (PK/PD) model that captured important aspects of the BP homeostasis mechanism. Four conceptual units characterized the feedback PD model: a sinusoidal BP set point, an effect compartment, a linear effect model, and a system response. To explore approaches for minimizing the BP increase, we coupled the PD model to a modified PK model to guide oral controlled-release (CR) development. The proposed PK/PD model captured the central tendency of the observed data. The simulated BP response obtained with theoretical release rate profiles suggested some amelioration of the peak BP response with CR. This triggered subsequent CR formulation development; we used actual dissolution data from these candidate CR formulations in the PK/PD model to confirm a potential benefit in the peak BP response. Though this paradigm has yet to be tested in the clinic, our model-based approach provided a common rational framework to more fully utilize the limited available information for advancing the program