Werawath Mahatthanatrakul

Ketoconazole increases plasma concentrations of antimalarial mefloquine in healthy human volunteers

Background:  Antimalarial mefloquine has a structure related to quinine. The major metabolite of quinine is 3‐hydroxyquinine formed by cytochrome P450 3A4 (CYP3A4). Ketoconazole, a potent inhibitor of CYP3A4, is known to markedly increase plasma concentrations of various co‐administered drugs including quinine.

Effect of Rifampin on Plasma Concentrations of Mefloquine in Healthy Volunteers

Mefloquine is a 4‐quinolinemethanol compound structurally related to quinine. Quinine is mainly metabolized by the cytochrome P450 3A4 isozyme (CYP3A4), whereas rifampin, a potent inducer of CYP3A4, is known to markedly decrease plasma quinine concentration. Our aim was to study the effect of rifampin on the pharmacokinetics of mefloquine, and explore a possible role of CYP3A4 on mefloquine metabolism.

Rifampin markedly decreases plasma concentrations of praziquantel in healthy volunteers

Praziquantel is extensively metabolized by the hepatic cytochrome P450 (CYP) enzymes. The CYP3A isoforms are likely to be major enzymes responsible for praziquantel metabolism. Rifampin (INN, rifampicin), a potent enzyme inducer of CYP‐mediated metabolism (especially CYP2C9, CYP2C19, and CYP3A4), is known to markedly decrease plasma concentrations and effects of a number coadministered drugs. The aim of this investigation was to study the possible pharmacokinetic interaction between rifampin and praziquantel.

Rifampin, a cytochrome P450 3A inducer, decreases plasma concentrations of antipsychotic risperidone in healthy volunteers.

Background:  Although cytochrome P450 (CYP) 2D6 is often thought to be the only CYP responsible for the metabolism of risperidone, many reports suggest that CYP3A may be involved too. Rifampin, a potent CYP3A inducer, has been known to markedly decrease plasma concentrations of various drugs, which are concomitantly administered during treatment.

LC determination of praziquantel in human plasma

A simple high-performance liquid chromatographic (HPLC) method for the determination of praziquantel in human plasma was developed and validated. The present method was described by adding drop-wise 0.2 M Zinc sulfate and acetonitrile to plasma sample for deproteinization. This method used a reversed-phase Spherisorb ODS 2 column (5 microm), 250 x 4.6 mm i.d. as a stationary phase with a mobile phase consisting of acetonitrile- methanol-water (36:10:54, v/v/v), a flow rate of 1.5 ml/min and UV detection wavelength of 217 nm. Diazepam was used as internal standard. The standard calibration curve was linear over the concentration range of 100-2000 ng/ml (r=0.999). The equation of a linear regression line was y=8.05E-04+7.25E-04x with slope and intercept values of 0.0007 and 0.0008, respectively. The limit of detection was 12.25 ng/ml and the limit of quantification was set at 100 ng/ml. The intra- and inter-day assay coefficients of variation (CV) were 3.0+/-1.7 and 6.3+/-1.9%, respectively. The percentage of recovery was 102.1+/-5.6. Therefore, the HPLC method described here was simple, rapid and reproducible since it did not require extraction and evaporation processes in sample preparation, which will reduce time-consuming or expensive sample preparation.

Pharmacokinetic interaction between ketoconazole and praziquantel in healthy volunteers.

Background: Praziquantel, a broad‐spectrum anthelminthic, has been reported to undergo extensive first‐pass metabolism by cytochrome P450 (CYP) enzymes in vivo. Ketoconazole, a potent CYP3A4 inhibitor, is known to markedly increase plasma concentrations of many co‐administered drugs. However, no data are available on the potential pharmacokinetic drug interaction between ketoconazole and praziquantel in humans.

Effect of cytochrome P450 3A4 inhibitor ketoconazole on risperidone pharmacokinetics in healthy volunteers

What is known and objective:  Risperidone is an atypical antipsychotic agent used for the treatment of schizophrenia. It is mainly metabolized by human cytochrome P450 CYP2D6 and partly by CYP3A4 to 9‐hydroxyrisperidone. Ketoconazole is used as a CYP3A4 inhibitor probe for studying drug–drug interactions. We aim to investigate the effect of ketoconazole on the pharmacokinetics of risperidone in healthy male volunteers.

Relative bioavailability and pharmacokinetic comparison of two 2-mg risperidone tablet formulations: A single dose, randomized-sequence, double-blind, 2-way crossover study in healthy male volunteers in thailand

BACKGROUND Data regarding the pharmacokinetic properties of risperidone in the Thai population are limited. A new generic tablet formulation was recently developed, but bioequivalence research is necessary to obtain marketing authorization for it in Thailand. OBJECTIVE The aim of this study was to evaluate and compare the pharmacokinetic properties of risperidone and its active metabolite, 9-hydroxyrisperidone (which reportedly contributes to the drugs pharmacodynamic effects), in a newly developed generic tablet formulation (test) and a branded formulation (reference) in healthy, fasting, male Thai volunteers. METHODS A single-dose, randomized-sequence, double-blind, 2-way crossover design was used in this study. The study took place from October 21 through November 28, 2007. After a ≥10-hour overnight fast, volunteers were orally administered one 2-mg risperidone tablet, either the test formulation (Condrug International Company, Ltd.) or the reference formulation-according to the randomization schedule-followed by a 14-day washout period and administration of the alternate formulation. Blood samples were collected over a period of 96 hours. Risperidone and 9-hydroxyrisperidone plasma concentrations were simultaneously determined using a validated HPLC/ion trap mass spectrometry method. The plasma concentration-time curves of the active moiety, risperidone, and 9-hydroxyrisperidone were generated for each volunteer, from which the C(max), T(max), AUC₀₋(last), AUC₀₋(∞), and t(½) were determined using noncompartmental analysis. The effects of formulation, period, sequence, and subject (within sequence) on pharmacokinetic parameters were analyzed using ANOVA. According to regulatory requirements set forth by Thailand, the Association of Southeast Asian Nations, and the US Food and Drug Administration, products meet the criteria for bioequivalence if the 90% CIs of the treatment ratios for C(max) and AUC are within the range of 0.80 to 1.25. Tolerability was assessed by patient interview, monitoring vital signs (ie, resting blood pressure, heart rate, body temperature), physical examination, and laboratory tests (ie, urinalysis, hematology, blood chemistry) before and after the study. RESULTS A total of 22 Thai male volunteers (mean [SD] age, 28.18 [8.27] years [range, 20.62-44.19 years]; weight, 62.43 [4.76] kg [range, 55.03-76.02 kg]; and body mass index, 21.76 [2.07] kg/m² [range, 18.9924.91 kg/m²]) completed the study. The mean (SD) relative bioavailabilities of test to reference formulations determined from AUC of the active moiety, risperidone, and 9-hydroxyrisperidone were 1.06 (0.18), 1.07 (0.29), and 1.04 (0.17), respectively. The ANOVA suggested no statistically significant effect of formulation, period, or sequence on the studied pharmacokinetic parameters of the active moiety, risperidone, or 9-hydroxyrisperidone. The 90% CIs for the natural logarithm-transformed ratios of C(max), AUC₀₋(last), and AUC₀₋(∞) were as follows: for active moiety, 0.94 to 1.03, 0.98 to 1.11, and 0.98 to 1.10, respectively; for risperidone, 0.90 to 1.10, 0.96 to 1.13, and 0.96 to 1.14, respectively; and for 9-hydroxyrisperidone, 0.91 to 1.03, 0.97 to 1.10, and 0.96 to 1.09, respectively. All met the criteria for bioequivalence. The most commonly reported adverse events (AEs) were somnolence (100.0%), orthostatic hypotension (13.6%), headache (4.5%), and syncope (2.3%). AEs were mild and disappeared within 1 day. No volunteers withdrew from the study because of AEs. CONCLUSIONS The single-dose pharmacokinetic data in this small, all-male, selected sample of fasting, healthy volunteers met Thailands regulatory criteria for assuming bioequivalence of the tested generic and reference 2-mg risperidone tablets. Both formulations were well tolerated.

Pharmacokinetic Interactions between Ciprofloxacin and Itraconazole in Healthy Male Volunteers

Objective. To investigate the pharmacokinetic interaction between ciprofloxacin and itraconazole in healthy male volunteers. Methods. Ten healthy male volunteers were assigned into a 2‐sequence, 3‐period pharmacokinetic interaction study. In phase 1, all subjects were randomly assigned to receive 500 mg of ciprofloxacin alone and 200 mg of itraconazole alone twice daily for 7 days with a 14 day wash‐out period in a crossover design. Phase 2 was performed 14 days after finishing phase 1, all subjects received 500 mg of ciprofloxacin in combination with 200 mg of itraconazole twice daily for 7 days. Ciprofloxacin and itraconazole pharmacokinetics were studied and adverse effects noted. Results. Ciprofloxacin significantly increased the Cmax and AUC0 − ∞ of itraconazole by 53.13% and 82.46%, respectively. The half‐life and CL of itraconazole were not changed significantly. The combination of itraconazole and ciprofloxacin could therefore result in an increase in adverse drug reactions. Conversely, itraconazole had no significant effect on the pharmacokinetics of ciprofloxacin. Conclusion. Ciprofloxacin decreases the metabolism of itraconazole, most likely through inhibition of CYP3A4. The dosage of itraconazole should be reduced and its therapeutic outcome should be monitored closely when these two agents are concomitantly administered. Copyright

Bioequivalence study of a generic quetiapine in healthy male volunteers

AIM To study the bioequivalence of a generic quetiapine (Quantia 200, manufactured by the Unison Laboratories Co., Ltd., Bangkok, Thailand) and the innovator product (Seroquel, AstraZeneca, Macclesfield, UK). VOLUNTEERS AND METHODS The study was a randomized, 2-way crossover design with a 2-week washout period in 24 healthy Thai male volunteers. After a single 200 mg oral dosing, serial blood samples were collected at appropriate interval up to 48 h. Plasma quetiapine concentrations were determined by high-performance liquid chromatography (HPLC). Pharmacokinetic parameters were estimated using the WinNonlin software with noncompartment model analysis. Comparative bioequivalence between the two formulations was determined by analysis of variance (ANOVA) for 2-way crossover design. RESULTS The mean +/- SD of maximum plasma concentration (Cmax), the area under the plasma concentration-time curve from 0 - 48 h (AUC0-48) and the area under the plasma concentration-time curve from 0 to infinity (AUC0-inf) of Quantia 200 vs. Seroquel were 886.60 +/- 356.50 vs. 811.34 +/- 323.37 ng/ml; 3,754.41 +/- 1,453.00 vs. 3,420.00 +/- 1,229.6 ng x h/ml and 4,015.35 +/- 1,528.25 vs. 3,769.45 +/- 1,296.69 ng x h/ml, respectively. Time to reach Cmax (tmax) of Quantia 200 and Seroquel were 1.08 +/- 0.778 and 1.10 +/- 0.79 h, respectively, and thus not significantly different. The 90% confidence interval of the ratios of the logarithmically transformed of Cmax, AUC0-48 and AUC0-inf were 98.21 - 124.37%, 94.43 - 117.03% and 94.77 - 116.61%, respectively, which were within the acceptable range of 80 - 125%. Power of the test for Cmax, AUC0-48 and AUC0-inf was 92.1%, 96.9% and 97.4%, respectively. CONCLUSION Quantia 200, used in this study, was bioequivalent to Seroquel in terms of both the rate and extent of absorption.