Bioequivalence of indinavir capsules in healthy volunteers

Asian Biomedicine Vol. 4 No. 1 February 2010; 95-101 Original article Bioequivalence of indinavir capsules in healthy volunteers Suvatna Chulavatnatola, Kumthorn Malathumb, Sasisopin Kiertiburanakulb, Kittisak Sriphac, Pojawon Lawanprasertd aDepartment of Pharmacy, Faculty of Pharmacy, bDepartment of Medicine, Faculty of Medicine, Ramathibodi Hospital, cDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, dDepartment of Manufacturing Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand Background: Indinavir, one component in the HAART regimen, plays an important role in the current treatment of HIV-infection and AIDS. Availability and accessibility of qualified generic indinavir to patients may be the keys for the success of treatment. Objective: Compare the rate and extent of absorption of a generic indinavir formulation with those of an original formulation in healthy Thai volunteers. Method: A randomized, two-period, two-treatment, two-sequence, crossover study with a two-week washout period was performed. A single dose of 2x400 mg indinavir capsules of each formulation was administered to 24 volunteers after an overnight fast. Indinavir plasma concentrations up to 10 hours postdose were determined using high-performance liquid chromatography. Relevant pharmacokinetic parameters were derived and tested for statistically significant differences using ANOVA and criteria of bioequivalence determination were applied. Results: No statistically significant differences were demonstrated for pharmacokinetic parameters including Cmax, Tmax, AUC0-t, and AUC0-∞ derived from the two formulations (n=23, p>0.05). The criteria of bioequivalence determination i.e., the 90% confidence intervals on the mean ratio (generic/original formulation) of natural logarithmtransformed values of Cmax, AUC0-t and AUC0-∞ were 86.3-106.5%, 94.0-108.5%, and 93.9-108.5%, respectively. Conclusion: As the mean ratios of Cmax, AUC0-t and AUC0-∞ of the generic and original formulations were entirely within the guideline range of bioequivalence (80.0-125.0%), the two formulations were considered bioequivalent in terms of rate and extent of absorption.

Pharmacokinetics of levofloxacin in healthy Thai male volunteers.

The pharmacokinetics of levofloxacin, a new fluoroquinolone, were investigated in 12 healthy Thai male volunteers with an average age (SD) of 22.92 (2.50) years. A single oral dose of 300 mg or 500 mg levofloxacin was given to subjects following an 8- hour overnight fast. The drug was given in a controlled, randomized, 2 x 2 crossover design with a 1 week washout period. Venous blood samples were drawn prior to and from 0.25 up to 48 hours after dosing. Plasma levofloxacin concentrations were determined by HPLC assay. The pharmacokinetics of levofloxacin were well described by a linear, 2-compartment open model with first-order absorption with lag time and first-order elimination. Mean +/- SEM of Cmax after 300 mg and 500 mg dose was 4.83 +/- 0.33 and 7.75 +/- 0.71 micrograms/mL, respectively. Tmax ranged from 0.7 to 0.8 hours for both doses. Mean +/- SEM of AUC0-infinity was 35.77 +/- 2.06 micrograms x h/mL for 300 mg dose and 61.57 +/- 2.84 micrograms x h/mL for 500 mg dose. High distribution with VSS/F value of approximately 1.5 L/kg was demonstrated after both doses. Mean +/- SEM of CL/F value was 8.64 +/- 0.41 L/h and 8.31 +/- 0.37 L/h for a 300-mg and a 500-mg dose, respectively. Long t1/2 beta of 7 to 8 hours with the mean residence time of 10.43 +/- 0.43 hours and 10.49 +/- 0.38 hours after 300 mg and 500 mg dose, respectively, was observed. The results suggested that an oral 300 mg dose once daily provides sufficient Cmax to cover most Gram-negative and atypical bacteria (median MIC90 0.032-0.5 microgram/mL) common in mild to moderate respiratory tract infections or complicated urinary tract infections and Gram-positive bacteria (median MIC90 0.5 microgram/mL) common in skin and soft tissue infections. For severe cases or Streptococcus pneumoniae (MIC90 2 micrograms/mL) infection, a 500-mg dose should be recommended.

The period prevalence of catamenial epilepsy at Prasat Neurological Institute, Bangkok.

The study was performed to assess the period prevalence of catamenial epilepsy in Thai female epileptic patients. Such a condition is defined as seizures related to menstruation which occur for at least 2 consecutive months within 1 patient during 4 days prior to and/or 6 days after the onset of menstruation. Patients with regular menstruation aged between 15-50 years attending the Out-Patient Department of Prasat Neurological Institute in Bangkok from 1 November, 1995 to 31 January, 1996 were recruited. Patients and/or their relatives were interviewed directly or by telephone using a questionnaire concerning menstrual history, seizures related to menstruation and they were requested to record these data for 2 further consecutive months. In cases where the interview could not be directly performed, a mailed questionnaire was used instead. All information was considered together with information reviewed from the OPD cards. Forty-six from 467 epileptic patients were considered to have catamenial epilepsy. The period prevalence thus was 98.5 in 1,000 women at risk and the mode of frequency of seizure occurrence was 2 days before menstruation. Generalized seizure was found more common in these patients than partial seizure. In particular, general tonic-clonic seizure and complex partial seizure were the most common for each type, respectively. About 70 per cent of the patients used more than 1 anti-convulsant drugs to control their seizures. Some have received other drug supplements to relieve seizure exacerbation but only mild improvement was observed. No change in body weights measured in 2 or 1 day before menstruation, on the first menstrual day and in 1 day after menstruation was demonstrated in all patients. The results suggest that catamenial epilepsy is one of the clinically significant problems of seizure control in Thai female epileptic patients and multifactors may be involved in this condition.

Bioavailability of phenytoin sodium capsules available in Thailand. Part II: In vivo study.

Four phenytoin brands, dilantin and three local brands (brand A, B and C) were selected for the bioavailability study. The study was carried out in 16 healthy male Thai volunteers with the average age of 21 years old. A single oral dose of 300 mg (three capsules of 100-mg) phenytoin sodium was given to subjects following an 8 hour-overnight fast. The tested drugs were given in a single-blind randomized crossover with at least 2 weeks of washout period. Venous blood samples of approximately 5 ml were drawn before medication and at 1, 2, 4, 6, 8, 10, 12, 24, 48 and 72 hours post dosing. Plasma phenytoin concentrations were determined by HPLC assay. The pharmacokinetic parameters were calculated from the plasma-concentration time curve of an innovator brand, dilantin, by PCNONLIN program. Elimination rate constant and half-life were 0.2 h-1 and 19 h, respectively. The maximum concentration (Cmax) and time to peak (Tmax) were 1.98 micrograms/ml and 9.6 h, respectively. Bioavailability study was determined by comparing the area under the plasma concentration time curve (AUC), maximum plasma concentration (Cmax) and time to reach maximum plasma concentration (Tmax) by using ANOVA. The result indicated that two local brands (brand A and brand C) were not bioequivalent to the innovator in terms of Cmax and AUC0-alpha, whereas Tmax was not significantly different among these 4 brands. Cmax and AUC of brand A and C were significantly higher than the innovator brand. In addition, the plasma concentration time profile of brand C was also different from other brands with the steep peak which yielded a Cmax value double that of the Cmax of the innovator. However, brand B (from Research and Development Institute, Government Pharmaceutical Organization) was bioequivalent to dilantin after 4 times of product formulation adjustment. This present study demonstrated that the local products (brand A and brand C) were not bioequivalent with the innovator. Thus, the interchange from one brand to another must be performed cautiously or should be avoided, otherwise phenytoin blood levels should be monitored closely together with the clinical signs and symptoms of the patients.