Sanjeev Kaul

Model-Based Approach To Characterize Efavirenz Autoinduction and Concurrent Enzyme Induction with Carbamazepine

ABSTRACT Characterization of the time course and magnitude of enzyme induction due to multiple inducers is important for interpretation of clinical data from drug-drug interaction studies. A population interaction model was developed to quantify efavirenz autoinduction and further induction with concurrent carbamazepine coadministration. Efavirenz concentration data in the absence and presence of carbamazepine following single- and multiple-dose oral administrations in healthy subjects were used for model development. The proposed model was able to describe the time-dependent efavirenz autoinduction and the further induction with carbamazepine when the agents were combined. The estimated population averages of efavirenz oral clearance were 5.5, 9.4, 14.4, and 16.7 liters/h on days 1, 14, and 35 and at steady state for the interaction, respectively, for efavirenz monotherapy for 2 weeks followed by the coadministration of carbamazepine for 3 weeks. The estimated times to 50% of the steady state for efavirenz autoinduction and for the induction resulting from the concurrent administration of efavirenz and carbamazepine were similar (around 10 to 12 days). With this model-based analysis, efavirenz exposures can be projected prior to and at the steady state of induction, allowing a better understanding of the time course and magnitude of enzyme induction.

Lack of Effect of Simultaneously Administered Didanosine Encapsulated Enteric Bead Formulation (Videx EC) on Oral Absorption of Indinavir, Ketoconazole, or Ciprofloxacin

ABSTRACT Didanosine formulation that contains a buffer to prevent it from acid-mediated degradation can result in a significant decrease in the oral absorption of certain drugs because of interactions with antacids. An enteric formulation of didanosine is unlikely to cause such drug interactions because it lacks antacids. This study was undertaken to determine whether the enteric bead formulation of didanosine (Videx EC) influences the bioavailability of indinavir, ketoconazole, and ciprofloxacin, three drugs that are representative of a broader class of drugs affected by interaction with antacids. Healthy subjects of either gender were enrolled in three separate open-label, single-dose, two-way crossover studies. Subjects were randomized to treatment A (800 mg of indinavir, 200 mg of ketoconazole, or 750 mg of ciprofloxacin) or treatment B (same dose of indinavir, ketoconazole, or ciprofloxacin, but with 400 mg of didanosine as an encapsulated enteric bead formulation). A lack of interaction was concluded if the 90% confidence interval (CI) of the ratio of the geometric means of log-transformed Cmax and AUC0-∞ values (i.e., values for the area under the concentration-time curve from time zero to infinity) of indinavir, ketoconazole, and ciprofloxacin were contained entirely between 0.75 and 1.33. For indinavir (n = 23), the point estimate (90% CI; minimum, maximum) of the ratios of Cmax and AUC0-∞ values were 0.99 (0.91, 1.06) and 0.96 (0.91, 1.02), respectively. In the ketoconazole study, 3 of 24 subjects showed anomalous absorption of ketoconazole (i.e., an ∼8-fold-lower AUC compared to historical data), which was the reference treatment. A post hoc analysis performed after these three subjects were excluded indicated that the point estimates (90% CI) of the ratios of Cmax and AUC0-∞ values were 0.99 (0.86, 1.14) and 0.97 (0.85, 1.10), respectively. For ciprofloxacin (n = 16), the point estimate (90% CI) of the ratios of Cmax and AUC0-∞ values were 0.92 (0.79, 1.07) and 0.91 (0.76, 1.08), respectively. All three studies clearly indicated a lack of interaction. The Tmax and t1/2 for indinavir, ketoconazole, and ciprofloxacin were similar between treatments. Our results showed that the lack of interaction of didanosine encapsulated enteric bead formulation with indinavir, ketoconazole, and ciprofloxacin indicates that this enteric formulation of didanosine can be concomitantly administered with drugs whose bioavailability is known to be reduced by interaction with antacids.

A phase I study of etoposide phosphate administered as a daily 30‐minute infusion for 5 days

To determine the maximum tolerated dose, toxicities, kinetics, and disposition of etoposide phosphate when administered as a daily 30‐minute infusion for 5 days.

Phase I and pharmacokinetic study of etoposide phosphate

Etoposide phosphate (EP) is a water-soluble derivative of etoposide (VP-16), a semisynthetic podophyllotoxin which is useful in the treatment of a wide variety of hematological malignancies and solid tumors. Because etoposide is poorly water soluble, it must be dissolved in a variety of organic solvents and given in relatively large volumes of saline. EP is rapidly converted to the parent drug in vivo and has been shown to be active in animal studies. We performed a phase I pharmacokinetic study in 27 patients. Three patients each received an etoposide-equivalent dose of 50 or 75 mg/m2 each day by i.v. bolus (5 min) daily for 5 days and 21 patients received a dose equivalent to 100 mg/m2 of etoposide each day for 5 days. Non-compartmental pharmacokinetic data were obtained for 22 of the patients. As with previous studies, EP behaves as a prodrug of etoposide. The Cmax (25.3–42.5 μg/ml) increased linearly, while AUCint (75.8–156 h μg/ml) of etoposide increased proportionately with dose (50–100 mg/m2 of etoposide equivalents). Time to achieve Cmax corresponded to the end of the 5 min injection, indicating a rapid formation of etoposide from EP. Mean etoposide phosphate/etoposide Cmax and AUCint ratios were 0.08 or less and 0.003, respectively, indicating that the major circulating molety in plasma was etoposide. Parameters such as MRT, T1/2, CL/F, CLR, Vss/F and %UR were dose independent. The toxicities of EP were virtually identical to those seen with etoposide, with dose-related myelosuppression, alopecia and stomatitis. Severe neutropenia was the dose-limiting toxicity. No significant problems with hypotension or allergic reactions were observed. No problems, difficulties or complications were observed as a result of bolus (5 min) administration. On the basis of phase I toxicity data, we recommend an etoposide equivalent starting dose of 100 mg/m2/day for 5 days in previously untreated patients who have an excellent performance status. In patients who have had one or more prior chemotherapy regimens, extensive prior radiation therapy or moderately impaired performance status, we recommend an etoposide phosphate starting dose of 75 mg/m2/day for 5 days with courses repeated at 3 week intervals.

Bioavailability in healthy adults of efavirenz capsule contents mixed with a small amount of food

PURPOSEnThe effect of mixing the contents of efavirenz capsules (sprinkles) with a small amount of food on the bioavailability and pharmacokinetics of efavirenz in healthy adults was evaluated.nnnMETHODSnIn a randomized, three-period, crossover study, 24 healthy adult subjects were divided equally into two groups. Group I received treatments A, B, and C, and those in group II received treatments A, D, and E. Treatment A was three efavirenz 200-mg intact capsules under fasting conditions. Treatments B, C, D, and E were three efavirenz 200-mg capsule contents mixed with two teaspoons of applesauce, grape jelly, yogurt, or infant formula, respectively. A single dose was given on days 1, 21, and 41. The steady-state mean maximum observed concentration, time of maximum observed concentration, area under the concentration-time curve (AUC) half-life, taste, and safety were assessed.nnnRESULTSnThe AUC after administration of a single 600-mg dose of efavirenz sprinkles mixed with two teaspoons of any of the food vehicles to healthy adults was bioequivalent to a 600-mg efavirenz dose given as intact capsules under fasting conditions. Subjects rated efavirenz mixed with grape jelly as the most palatable. Adverse events and laboratory abnormalities were similar for all treatments.nnnCONCLUSIONnThe AUC of efavirenz 600 mg administered as capsule sprinkles with two teaspoons of applesauce, grape jelly, yogurt, or infant formula was bioequivalent to a single dose of efavirenz 600 mg given as intact capsules under fasting conditions in healthy adults.

DISPOSITION OF [1'-14C]STAVUDINE AFTER ORAL ADMINISTRATION TO HUMANS

The disposition of stavudine, a potent and orally active nucleoside reverse transcriptase inhibitor, was investigated in six healthy human subjects. Before dosing humans with [1′-14C]stavudine, a tissue distribution study was performed in Long-Evans rats. Results from this study showed no accumulation of radioactivity in any of the tissues studied, indicating that the position of the 14C-label on the molecule was appropriate for the human study. After a single 80-mg (100 μCi) oral dose of [1′-14C]stavudine, approximately 95% of the radioactive dose was excreted in urine with an elimination half-life of 2.35 h. Fecal excretion was limited, accounting for only 3% of the dose. Unchanged stavudine was the major drug-related component in plasma (61% of area under the plasma concentration-time curve from time zero extrapolated to infinite time of the total plasma radioactivity) and urine (67% of dose). The remaining radioactivity was associated with minor metabolites, including mono- and bis-oxidized stavudine, glucuronide conjugates of stavudine and its oxidized metabolite, and an N-acetylcysteine (NAC) conjugate of the ribose (M4) after glycosidic cleavage. Formation of metabolite M4 was shown in human liver microsomes incubated with 2′,3′-didehydrodideoxyribose, the sugar base of stavudine, in the presence of NAC. In addition, after similar microsomal incubations fortified with GSH, two GSH conjugates, 3′-GS-deoxyribose and 1′-keto-2′,3′-dideoxy-3′-GS-ribose, were observed. This suggests that 2′,3′-didehydrodideoxyribose underwent cytochrome P450-mediated oxidation leading to an epoxide intermediate, 2′,3′-ribose epoxide, followed by GSH addition. In conclusion, absorption and elimination of stavudine were rapid and complete after oral dosing, with urinary excretion of unchanged drug as the predominant route of elimination in humans.

PII-40Model-based approach to characterize auto-induction: Experience with efavirenz

Drug metabolising enzymes can be self‐induced or co‐drug induced leading to lower systemic exposures and reduced accumulation upon repeated dosing. The study was aimed at developing a generic model to characterize the dynamics of the auto‐induction (AI) with efavirenz (EFV) as a model drug. EFV is a non‐nucleoside reverse transcriptase inhibitor for the treatment of HIV. It is primarily metabolised by CYP3A4 and 2B6 and exhibits AI.