Clopidogrel is a prodrug that has to be converted in vivo to its active metabolite by cytochrome (CYP)P450 iso-enzymes. As calcium channel blockers (CCBs) are inhibitors of CYP3A4, concomitant use of these drugs might play a role in the wide inter-individual variability in the response to clopidogrel. However, some CCBs also have strong inhibitory effects on the drug transporter P-glycoprotein (Pgp), which mediates clopidogrel's intestinal absorption. It was the aim of this study to evaluate the effect of co-administration of Pgp-inhibiting and non-Pgp-inhibiting CCBs on on-clopidogrel platelet reactivity in patients on dual antiplatelet therapy undergoing elective percutaneous coronary intervention (PCI). In a total of 623 consecutive patients undergoing elective PCI treated with clopidogrel and aspirin, platelet reactivity to 5 and 20 muM adenosine diphospate (ADP) and clopidogrel poor-response (defined as > 70% platelet aggregation to 20 muM ADP) were evaluated by light transmittance aggregometry. A total of 222 patients (35.6%) were on CCB treatment, of which 98 used Pgp-inhibiting CCBs (verapamil, nifedipine, diltiazem, barnidipine) and 124 patients used the non-Pgp-inhibiting CCB amlodipine. Adjusted mean ADP-induced on-clopidogrel platelet reactivity was significantly higher in both users of Pgp-inhibiting CCBs and amlodipine as compared to CCB non-users (all p<0.05). However, only the use of amlodipine was significantly associated with a 2.3-fold increased risk of clopidogrel poor-response. This study demonstrates that concomitant use of Pgp-inhibiting CCBs and amlodipine increases on-clopidogrel platelet reactivity. Only amlodipine was associated with clopidogrel poor-response. The drug-drug interaction between clopidogrel and amlodipine might be more clinically relevant as compared to P-glycoprotein-inhibiting CCBs.

Tuberculosis (TB) remains a major global health problem. Inadequate exposure to TB drugs constitutes one of the main factors underlying suboptimal treatment response and development of resistance, as evidenced by results from: the in vitro hollow fibre model [1]; clinical studies on relationships between drug concentrations and response [2-5]; a pharmacogenetic trial [6]; and a recent meta-analysis [7].More specifically, these concentration-effect evaluations suggest that clinicians should prescribe higher doses of rifampicin [2,5], that acetylator status should be used to determine the dose of isoniazid [6,7], and that higher doses and exposures to pyrazinamide may increase efficacy [4,5].Clearly, such studies also underline the relevance of careful concentration-effect evaluations during the development of new TB drugs that will eventually be applied by clinicians all over the world.Finally, these studies support the concept of therapeutic drug monitoring (TDM) of TB drugs as applied by clinicians and pharmacists in selected centres around the world [8][9][10]. In contrast to administering the same fixed dose to all patients, TDM seeks to individualise drug doses, guided by measurement of serum (or plasma) drug concentrations.

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Although not all results for PTM with carbamazepine and valproic acid are within the commutability decision limits, a preference for human serum can be seen.