Effect of concurrently coadministered drugs on the pharmacokinetic/pharmacodynamic profile of centchroman, a nonsteroidal oral contraceptive, in rats

INTRODUCTION: Centchroman (international nonproprietary name: ormeloxifene) is a nonsteroidal selective estrogen receptor modulator, oral contraceptive, anticancer and antiosteoporotic agent that is intended for long-term use by women. In view of the vast clinical applications and interactions of steroidal oral contraceptives with commonly used therapeutic agents, the interaction potential of certain concomitantly administered therapeutic agents was investigated in terms of postcoital contraceptive efficacy (pharmacological) and the pharmacokinetic profile of centchroman in female Sprague-Dawley rats. The coadministered drugs used in the study were ciprofloxacin, cefixime, amoxicillin, metronidazole, amlodipine, atenolol, theophylline, metformin, pioglitazone and glibenclamide. MATERIALS AND METHODS: The pharmacological activity of centchroman was evaluated in sperm-positive female rats at 1.5 mg/kg, with or without coadministered drugs. Rats were sacrificed on Day 10 postcoitus, and autopsy was performed to check for the presence or absence of implantations. The estrogenic and antiestrogenic activities of centchroman were evaluated in immature ovariectomized rats. Pharmacokinetic interaction was studied in normal female rats with or without coadministered drugs. Serum samples were taken over 120 h and analyzed using a validated high-performance liquid chromatography method to generate the pharmacokinetic profile of centchroman. Pharmacokinetic parameters were estimated using noncompartmental analysis, and the results were compared. RESULTS: In pharmacological interaction studies, centchroman alone showed a 100% success rate when given alone or in the presence of coadministered drugs. The only exception was amoxicillin coadministration, with 66% rats in the group showing resorbed implantations. Further investigation with amoxicillin in ovariectomized immature rats indicates no alteration in the estrogenic and antiestrogenic profiles of centchroman. In pharmacokinetic interaction studies, most of the therapeutic agents affected the rate and extent of absorption of centchroman. In other pharmacokinetic parameters, clearance (CL) remained unchanged; however, there was decrease in bioavailability (F) and volume of distribution (V(d)) in some situations. CONCLUSIONS: The results indicate that there is no direct link between the altered pharmacokinetics of centchroman and the failure of pharmacological effect. The pharmacological interaction with amoxicillin could not be explained on the basis of alteration in the estrogenic and antiestrogenic activities of centchroman, indicating that different mechanisms are involved. The findings, however, suggest that amoxicillin coadministration may result in pharmacological interaction with centchroman and that caution should be taken in clinical practice.     

Evaluation of the safety and immunogenicity of Plasmodium falciparum apical membrane antigen 1, merozoite surface protein 1 or RTS,S vaccines with adjuvant system AS02A administered alone or concurrently in rhesus monkeys

In an effort to broaden the immune response induced by the RTS,S/AS02_A,vaccine, we have evaluated the immunogenicity of the RTS,S antigen when combined with MSP1₄₂ and with AMA1, antigens derived from the asexual blood stage. The objectives of this study were (i) to determine whether MSP1₄₂ and AMA1 vaccines formulated with the AS02_A Adjuvant System were safe and immunogenic in the rhesus monkey model; (ii) to investigate whether MSP1₄₂ or AMA1 induced immune interference to each other, or to RTS,S, when added singly or in combinations at a single injection site; (iii) in the event of immune interference, to determine if this could be reduced when antigens were administered at separate sites. We found that MSP1₄₂ and AMA1 were safe and immunogenic, eliciting antibodies, and Th1 and Th2 responses using IFN-γ and IL-5 as markers. When malaria antigens were delivered together in one formulation, MSP1₄₂ and RTS,S reduced AMA1-specific antibody responses as measured by ELISA however, only MSP1₄₂ lowered parasite growth inhibitory activity of anti-AMA1 antibodies as measured by in vitro growth inhibition assay. Unlike RTS,S, MSP1₄₂ significantly reduced AMA1 IFN-γ and IL-5 responses. MSP1₄₂ suppression of AMA1 IFN-γ responses was not seen in animals receiving RTS,S + AMA1 + MSP1₄₂ suggesting that RTS,S restored IFN-γ responses. Conversely, AMA1 had no effect on MSP1₄₂ antibody and IFN-γ and IL-5 responses. Neither AMA1 alone or combined with MSP1₄₂ affected RTS,S antibody or IFN-γ and IL-5 responses. Immune interference by MSP1₄₂ on AMA1 antibody responses was also evident when AMA1, MSP1₄₂ and RTS,S were administered concurrently at separate sites. These results suggest that immune interference may be complex and should be considered for the design of multi-antigen, multi-stage vaccines against malaria.