Population pharmacokinetics of vancomycin in premature Malaysian neonates: identification of predictors for dosing determination.

The present study determined the pharmacokinetic profile of vancomycin in premature Malaysian infants. A one-compartment infusion model with first-order elimination was fitted to serum vancomycin concentration data (n = 835 points) obtained retrospectively from the drug monitoring records of 116 premature newborn infants. Vancomycin concentrations were estimated by a fluorescence polarization immunoassay. Population and individual estimates of clearance and distribution volume and the factors which affected the variability observed for the values of these parameters were obtained using a population pharmacokinetic modeling approach. The predictive performance of the population model was evaluated by visual inspections of diagnostic plots and nonparametric bootstrapping with replacement. Dosing guidelines targeting a value of > or =400 for the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC(24)/MIC ratio) were explored using Monte Carlo simulation. Body size (weight), postmenstrual age, and small-for-gestational-age status are important factors explaining the between-subject variability of vancomycin pharmacokinetic parameter values for premature neonates. The typical population parameter estimates of clearance and distribution volume for a 1-kg premature appropriate-for-gestational-age neonate with a postmenstrual age of 30 weeks were 0.0426 liters/h and 0.523 liters, respectively. There was a 20% reduction in clearance for small-for-gestational-age infants compared to the level for the appropriate-for-gestational-age control. Dosage regimens based on a priori target response values were formulated. In conclusion, the pharmacokinetic parameter values for vancomycin in premature Malaysian neonates were estimated. Improved dosage regimens based on a priori target response values were formulated by incorporating body size, postmenstrual age, and small-for-gestational-age status, using Monte Carlo simulations with the model-estimated pharmacokinetic parameter values.

A bioequivalence comparison of two formulations of rifampicin (300- vs 150-mg capsules): An open-label, randomized, two-treatment, two-way crossover study in healthy volunteers.

BACKGROUND: Rifampicin is a semisynthetic antibiotic derivative of rifamycin used worldwide for the treatment of various forms of tuberculosis. OBJECTIVE: The objective of this study was to compare, under fasting conditions in healthy volunteers, the rate and extent of absorption of a generic rifampicin capsule in oral dosage form versus the proprietary equivalent formulation for the purpose of registration approval of the test formulation. METHODS: This was an open-label, randomized, 2-treatment, 2-way crossover study with an 8-week washout period between the 2 study arms. Healthy volunteers received a 300-mg capsule of the test formulation (Idaman Pharma Manufacturing Sdn. Bhd.) or two 150-mg capsules of the reference formulation. Blood samples were collected predose and at 45 minutes and 1.25, 1.5, 2, 2.25, 2.5, 3, 3.5, 4, 6, 8, 10, 12, and 24 hours postdose. Plasma concentrations of rifampicin and its metabolite, 25-desacetyl rifampicin, were analyzed using a validated HPLC method. The formulations were considered bioequivalent if the 90% CIs for C(max) and AUC were within the predetermined bioequivalence range (80%-125%, according to the guidelines of the US Food and Drug Administration, or 75%-133% for Cmax only, as set by the European Commission-European Medicines Agency and the National Pharmaceutical Control Bureau of Malaysia). Tolerability was assessed by verbally questioning subjects regarding their well-being and any feelings of discomfort. All events reported by the subjects (serious or mild) were recorded on adverse-event forms. RESULTS: Fourteen healthy subjects (10 males, 4 females) with a mean age of 22.6 years (range, 20-28 years) and a mean body mass index of 22.2 kg/m² (range, 18.3-29.9 kg/m²) were enrolled in the study; all 14 completed the trial as outlined in the protocol. The mean values for C(max), T(max) , AUC0₋24, and AUC0₋(∞)) with the test formulation of rifampicin were 7.20 µg/mL, 1.32 hours, 37.12 µg/mL · h, and 39.69 µg/mL · h, respectively; for the reference formulation, the values were 7.65 µg/mL, 1.71 hours, 38.92 µg/mL · h, and 42.24 µg/ mL · h. For 25-desacetyl rifampicin, the mean values for C(max), T(max), AUC0₋24, and AUC0₋(∞)) with the test formulation were 0.63 µg/mL, 3.45 hours, 4.92 µg/mL · h, and 6.27 µg/mL · h; for the reference formulation, the values were 0.7 µg/mL, 3.27 hours, 5.23 µg/mL · h, and 6.84 µg/mL · h. For rifampicin, the 90% CIs for the test formulation/reference formulation ratio for the logarithmic transformations of both C(max) and AUC0₋(∞)) were within the bioequivalence limit of 80% to 125% (80.9109.7 and 80.7-103.2, respectively). For 25-desacetyl rifampicin, the 90% CI for the test formulation/reference formulation ratio for the logarithmic transformations of AUC0₋24 (80.0-104.7) was within the bioequivalence limit of 80% to 125%. However, the 90% CI for C(max) (78.4-102.2) was outside this limit but still within the acceptance limit for Cmax when adhering to the bioequivalence range of 75% to 133%. No adverse events were reported during the study. CONCLUSIONS: This study found that the 300-mg test capsule and the 150-mg reference capsules of rifampicin met the regulatory criteria for assuming bioequivalence in these fasting healthy volunteers. Both formulations appeared to be well tolerated in the population studied.

Tuberculin skin testing among healthcare workers in the University of Malaya Medical Centre, Kuala Lumpur, Malaysia.

OBJECTIVES: To determine the occupational risk of Mycobacterium tuberculosis infection among healthcare workers (HCWs) and to examine the utility of tuberculin skin testing in a developing country with a high prevalence of bacille Calmette-Guerin vaccination. DESIGN: Tuberculin skin test (TST) survey. SETTING: A tertiary-care referral center and a teaching hospital in Kuala Lumpur, Malaysia. PARTICIPANTS: HCWs from medical, surgical, and orthopedic wards. INTERVENTION: Tuberculin purified protein derivative RT-23 (State Serum Institute, Copenhagen, Denmark) was used for the TST (Mantoux method). RESULTS: One hundred thirty-seven (52.1%) and 69 (26.2%) of the HCWs tested had indurations of 10 mm or greater and 15 mm or greater, respectively. Medical ward HCWs were at significantly higher risk of a positive TST reaction than were surgical or orthopedic ward HCWs (odds ratio, 2.18; 95% confidence interval, 1.33 to 3.57; P = .002 for TST positivity at 10 mm or greater) (odds ratio, 2.61; 95% confidence interval, 1.44 to 4.70; P = .002 for TST positivity at 15 mm or greater). A previous TST was a significant risk factor for a positive TST reaction at either 10 mm or greater or 15 mm or greater, but a duration of employment of more than 1 year and being a nurse were only significantly associated with a positive TST reaction at a cut-off point of 15 mm or greater. CONCLUSIONS: HCWs at the University of Malaya Medical Centre had an increased risk for M. tuberculosis infection that was significantly associated with the level of occupational tuberculosis exposure. A TST cut-off point of 15 mm or greater may correlate better with M. tuberculosis infection than a cut-off point of 10 mm or greater in settings with a high prevalence of bacille Calmette-Guerin vaccination.