Modification to improve efficiency of sampling schedules for BA/BE testing of FDC anti-tuberculosis drugs.
METHODS
The assessment of rifampicin (RMP) containing fixed-dose combination (FDC) formulations using in vivo bioequivalence testing is widely accepted. It would be advantageous for both the drug regulatory authorities and drug manufacturers, for optimum minimum blood testing time intervals that encompass all anti-tuberculosis active constituents in the FDC to be established.


OBJECTIVE
To determine the optimum blood sampling schedule for testing novel FDC anti-tuberculosis drugs, isoniazid, RMP, pyrazinamide and ethambutol


METHODS
The results of 12 different single-dose, two-way cross-over designs are presented. The studies determined the bioavailability and bioequivalence of RMP-containing FDCs, and conformed with the requirements of the South African national drug regulatory authority for each of the active constituents.


RESULTS
The pharmacokinetic parameters to determine bioavailability and the Hauschke method to determine bioequivalence revealed that a six-point time protocol, namely 0, 1, 2, 4, 6 and 8 h, provides a good approximation of the area under the curve, and that an 11-point time protocol of 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6 and 8 h provided information comparable to the conventional 15 time-points for FDCs containing up to four drugs.


CONCLUSIONS
The findings provide concrete economic benefit and convenience for quality assurance testing of existing and novel FDCs.
Gabriels
G A
GA
Division of Clinical Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Rondebosch, South Africa. ggabriel@uctgsh1.uct.ac.za
McIlleron
H
H
Smith
P J
PJ
Folb
P I
PI
Fourie
P B
PB
D000995:Antitubercular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D001800:Blood Specimen Collection / Q000379:methods*; D004977:Ethambutol / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage / Q000493:pharmacokinetics; D011718:Pyrazinamide / Q000008:administration & dosage / Q000493:pharmacokinetics; D011785:Quality Assurance, Health Care; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics; D013019:South Africa; D013810:Therapeutic Equivalency
D000995:Antitubercular Agents; D011718:Pyrazinamide; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin