COMPARATIVE PHARMACOKINETICS OF RIFAMPICIN AND 25-DESACETYL RIFAMPICIN IN HEALTHY VOLUNTEERS AFTER SINGLE ORAL DOSE ADMINISTRATION
DANIELA MARCHIDANU1, NICOLETA RADUCANU1*, DALIA SIMONA MIRON1, FLAVIAN ȘTEFAN RADULESCU1, VALENTINA ANUȚA1, ION MIRCIOIU2, IRINA PRASACU1
1University of Medicine and Pharmacy “Carol Davila”, Faculty of Pharmacy, 6 Traian Vuia street, 020956, Bucharest, Romania.
2University of Medicine and Pharmacy, Târgu Mureș, Romania.
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The in vivo evaluations were conducted as part of an open label, analytical
blinded, single dose, randomized, two treatments, two periods, two sequences, fast state,
crossover bioequivalence study. Plasma levels of rifampicin and des-ethylrifampicin were
determined using a validated HPLC method.
Non-compartmental analysis for determination of peak drug concentration
(Cmax), time to reach maximum plasma concentration (Tmax), the plasma half-life (t1/2),
the area under curve of measured plasma concentrations to the last sampling point (AUD)
and total area under curve (AUC) were performed with the software Kinetica 3.1
Compartmental analysis was performed using Topfit 2.0 software. Hierarchy of the
performance of compartmental models was established using Akaike, Schwarz and
Imbimbo criteria. Significance of difference between the values of the criteria was tested
using F-test.
The concentrations of metabolite were much smaller compared to the parent
drug. Absorption was very rapid, maxim concentration being reached in less than one hour
and the metabolism was fast. Twelve hours after administration, the plasma levels became
low, much under the therapeutic level. Tmax values were 2.2 h for parent drug and 3.8 for
metabolite. The difference was statistically significant and the result was the expected one.
The metabolite appeared in plasma later, consecutive to absorption and metabolism of the
parent drug. The correlation coefficient was poor. The cause of this lack of correlation
could be the high variability (CV%=49 %) of the parameter corresponding to the parent
drug. This result was considered as a consequence of the fact that rifampicin is mainly
excreted through the feces and only a small part is excreted through the urine. Variability of
the two compounds was similar, lower than the variability of all the other parameters.
Correlation of the values for parent drug and active metabolite was better than in case of
Tmax, but lower than in case of AUC and Cmax. The AUC values for metabolite were one
order of magnitude smaller, but it is important to note a better correlation between the two
active entities (r=0,66). The variation coefficients indicated that it is the case of a high
variability drug.
Since the parent drug has a great value of partition coefficient (logP=2,77), its
solubility in deep compartment has to be significant and the expected result was at least a
two-compartment model. The pharmacokinetic model which described the evolution of plasma level of both parent drug and metabolite was the mono-compartmental one.
Increasing the number of compartments didn’t improve significantly the modeling
performance.
The pharmacokinetics of rifampicin and its active metabolite after a single
administration in healthy volunteers does not impose an adjustment of therapeutic schedule
following a variable metabolism. High variability of plasma levels of rifampicin could arise
mainly from a high variability of absorption, distribution and elimination.
