In 2007, a consortium of European experts on tacrolimus (TAC) met to discuss the most recent advances in the drug/dose optimization of TAC taking into account specific clinical situations and the analytical methods currently available and drew some recommendations and guidelines to help clinicians with the practical use of the drug. Pharmacokinetic, pharmacodynamic, and more recently pharmacogenetic approaches aid physicians to individualize long-term therapies as TAC demonstrates a high degree of both between- and within-individual variability, which may result in an increased risk of therapeutic failure if all patients are administered a uniform dose. TAC has undoubtedly benefited from therapeutic drug monitoring, but interpretation of the blood concentration is confounded by the relative differences between the assays. Single time points, limited sampling strategies, and area under concentration-time curve have all been considered to determine the most appropriate sampling procedure that correlates with efficacy. Therapeutic trough TAC concentration ranges have changed since the initial introduction of the drug, while still maintaining adequate immunosuppression and avoiding drug-related adverse effects. Pharmacodynamic markers have also been considered advantageous to the clinician, which may better reflect efficacy and safety, taking into account the between-individual variability rather than whole blood concentrations. The choice of method, differences between methods, and potential pitfalls of the method should all be considered when determining TAC concentrations. The recommendations of this consensus meeting regarding the analytical methods include the following: encourage the development and promote the use of analytical methods displaying a lower limit of quantification (1 ng/mL), perform careful validation when implementing a new analytical assay, participate in external proficiency testing programs, promote the use of certified material as calibrators in high-performance liquid chromatography with mass spectrometric detection methods, and take account of the assay and intermethod bias when comparing clinical trial outcomes. It is also important to consider that TAC concentrations may also be influenced by other factors such as specific pharmacokinetic characteristics associated with the population, drug interactions, pharmacogenetics, adverse events that may alter TAC concentrations, and any change in the oral formulation that may result in pharmacokinetic changes. This meeting emphasized the importance of obtaining multicenter prospective trials to assess the efficacy of alternative strategies to TAC trough concentrations whether it is other single time points or area under the concentration-time curve Bayesian estimation using limited sampling strategies and to select, standardize, and validate routine biomarkers of TAC pharmacodynamics.

No abstract

Aims 1) To develop an estimate of oral clearance (CL Px /F) for the antianginal agent perhexiline based on the ratio of cis-OH-perhexiline metabolite/parent perhexiline plasma concentrations at steady-state C OHPx;ss =C Px;ss À Á . 2) To determine whether the ratio measured in the first fortnight of treatment C iOHPx =C i Px À Á may be used to guide patient dosing with perhexiline, a drug with a narrow therapeutic index, long half-life and saturable metabolism via CYP2D6. Methods Two retrospective studies were conducted reviewing patient records and data obtained from routine monitoring of plasma perhexiline and cis-OH-perhexiline concentrations.Results Study 1 (n=70). At steady-state, the frequency distributions of CL Px /F and C OHPx;ss /C Px;ss were consistent with CYP2D6 metabolism. Putative poor metabolizers (approximately 8%) were identified by CL Px /Fj50 ml min x1 or C OHPx;ss /C Px;ss O0.3. A group of patients with CL Px /Fi950 ml min x1 may have been ultra-rapid metabolizers. In this group, the high CL Px /F values suggest extensive first-pass metabolism and poor bioavailability. In patients with therapeutic plasma perhexiline concentrations (0.15-0.60 mg l x1 ), the variability in dose appeared directly proportional to CL Px /F (r 2 =0.741, P<0.0001). Study 2 (n=23).Px patients were tentatively identified as poor, extensive and ultra-rapid metabolizers, with CL Px /F of 23-72, 134-868 and 947-1462 ml min x1 , respectively, requiring doses of 10-25, 100-250 and 300-500 mg day x1 , respectively. Conclusions The cis-OH-perhexiline/perhexiline concentration ratio may be useful for optimizing individual patient treatment with the antianginal agent perhexiline.

No abstract

Lamotrigine (LTG) is one of the newer antiepileptic drugs which has been shown to have a spectrum of drug interactions (including with other epilepsy drugs) that can have a pronounced effect on LTG kinetics. The present study examined the LTG metabolic inhibition dose-response relationship with valproic acid (VPA) in eight patients with epilepsy with a view to using this to benefit the patient. This could benefit the patient not only by attaining higher plasma LTG concentrations with "standard" dosages of LTG, but also possibly by achieving better seizure control through providing a less variable peak-to-trough fluctuation in LTG concentrations as a result of extending the half-life of LTG. The dosages of VPA trialed were 0, 200, 500, and 1,000 mg/d which resulted in a mean increase in LTG area under the curve of 83.7 +/- 14.7% at 200 mg VPA/d, to and 160 +/- 37.9% at 1,000 mg VPA/d. The presence of concomitant enzyme inducers in some patients did not influence the percentage increase from baseline in half-life observed, although clearly those on inducers started from a lower absolute half-life as a result of the induction. The effect was shown to be quite variable, particularly at the highest dosage of VPA tested (1,000 mg/d), suggesting that this effect could be best applied with the support of the therapeutic drug monitoring laboratory determining plasma LTG concentrations to allow individualization of the LTG dosage.