In 2014, the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology called a meeting of international experts to provide recommendations to guide therapeutic drug monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice. EVR is a potent inhibitor of the mammalian target of rapamycin, approved for the prevention of organ transplant rejection and for the treatment of various types of cancer and tuberous sclerosis complex. EVR fulfills the prerequisites for TDM, having a narrow therapeutic range, high interindividual pharmacokinetic variability, and established drug exposure-response relationships. EVR trough concentrations (C0) demonstrate a good relationship with overall exposure, providing a simple and reliable index for TDM. Whole-blood samples should be used for measurement of EVR C0, and sampling times should be standardized to occur within 1 hour before the next dose, which should be taken at the same time everyday and preferably without food. In transplantation settings, EVR should be generally targeted to a C0 of 3-8 ng/mL when used in combination with other immunosuppressive drugs (calcineurin inhibitors and glucocorticoids); in calcineurin inhibitor-free regimens, the EVR target C0 range should be 6-10 ng/mL. Further studies are required to determine the clinical utility of TDM in nontransplantation settings. The choice of analytical method and differences between methods should be carefully considered when determining EVR concentrations, and when comparing and interpreting clinical trial outcomes. At present, a fully validated liquid chromatography tandem mass spectrometry assay is the preferred method for determination of EVR C0, with a lower limit of quantification close to 1 ng/mL. Use of certified commercially available whole-blood calibrators to avoid calibration bias and participation in external proficiency-testing programs to allow continuous cross-validation and proof of analytical quality are highly recommended. Development of alternative assays to facilitate on-site measurement of EVR C0 is encouraged.

Aims To review (retrospectively) the relationships between lamotrigine (LTG) dosage and plasma concentrations based on data generated in a routine therapeutic drug monitoring laboratory from a heterogeneous sample of patients with epilepsy. To distinguish patients taking concomitant anti-epileptic therapy which induced or inhibited drug metabolising enzymes, or a combination of both, together with LTG. To survey medical staff who use a routine LTG assay service with a view to establishing the utility of higher plasma LTG concentrations than those used in early clinical trials. Methods All patient assays for LTG received over a 12 month period (339 requests from 149 patients) were reviewed and relationships between dosage and concentration calculated and grouped according to concomitant antiepileptic drug therapy. The doctors requesting the tests were surveyed by questionnaire (n=40 of 67 responded). They were asked for details about the patient's seizure control, rationale used for LTG dosage adjustment and their acceptance of the proposed 'therapeutic range' adopted by the laboratory of 3-14 mg l −1 .Results Linear relationships were demonstrated between LTG dosage and concentration for the 3 treatment groups (LTG plus valproic acid (VPA), LTG plus enzyme inducing antiepileptic drugs, and LTG plus VPA and inducers), however, there were significant differences between groups ( P<0.001) with a 4.4 fold difference in dosage5concentration ratios between the LTG plus VPA group and the LTG plus inducers group. The questionnaire showed that the therapeutic range was well accepted by 88% of responders, none of whom considered this higher range to be wrong. Conclusions Metabolic inhibition by VPA was shown to have a marked effect on LTG kinetics, suggesting either a significant LTG dosage reduction is required if plasma LTG concentrations are elevated, or alternatively, higher plasma LTG concentrations could be attained from lower dosages. The higher therapeutic range adopted by the laboratory (3-14 mg l −1 ) was widely accepted and increasingly applied in clinical practice in the management of patients with epilepsy.

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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.

AimsTo explore a Bayesian approach for the pharmacokinetic analysis of sirolimus concentration data arising from therapeutic drug monitoring (poorly informative concentration-time point design), and to explore possible covariate relationships for sirolimus pharmacokinetics. MethodsSirolimus concentration-time data were available as part of routine clinical care from 25 kidney transplant recipients. Most samples were taken at or near the trough time point at steady state. The data were analyzed using a fully conditional Bayesian approach with PKBUGS (v 1.1)/WinBUGS (v 1.3). Features of the data included noncompliance and missing concentration measurements below the limit of sensitivity of the assay. Informative priors were used. ResultsA two-compartment model with proportional residual error provided the best fit to the data (consisting of 315 sirolimus concentration-time points). The typical value for the apparent clearance (CL/ F ) was 12.5 l h − 1 at the median age of 44 years. Apparent CL was found to be inversely related to age with a posterior probability of a clinically significant effect of 0.734. ConclusionsA population pharmacokinetic model was developed for sirolimus using a novel approach. Bayesian modelling with informative priors allowed interpretation of a significant covariate relationship, even using poorly informative data.

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The present study estimated the population pharmacokinetics of lamotrigine in patients receiving oral lamotrigine therapy with drug concentration monitoring, and determined intersubject and intrasubject variability. A total of 129 patients were analyzed from two clinical sites. Of these, 124 patients provided sparse data (198 concentration-time points); nine patients (four from a previous group plus five from the current group) provided rich data (431 points). The population analysis was conducted using P-PHARM (SIMED Scientific Software, Cedex, France), a nonlinear mixed-effect modeling program. A single exponential elimination model (first-order absorption) with heteroscedastic weighting was used. Apparent clearance (CL/F) and volume of distribution (V/F) were the pharmacokinetic parameters estimated. Covariate analysis was performed to determine which factors explained any of the variability associated with lamotrigine clearance. Population estimates of CL/F and V/F for lamotrigine generated in the final model were 2.14 +/- 0.81 L/h and 78.1 +/- 5.1 L/kg. Intersubject and intrasubject variability for clearance was 38% and 38%, respectively. The covariates of concomitant valproate and phenytoin therapy accounted for 42% of the intersubject variability of clearance. Age, gender, clinic site, and other concomitant antiepileptic drugs did not influence clearance. This study of the population pharmacokinetics of lamotrigine in patients using the drug clinically provides useful data and should lead to better dosage individualization for lamotrigine.

The use of alternative strategies to the traditional pre-dose/trough (C0) blood sampling for cyclosporine (CsA) therapeutic drug monitoring has the potential to revolutionize analytical practices which have, in many centers, been established for some 20 years. While the C0 sample has previously been recommended, current attitudes are increasingly proposing alternatives for assessing CsA exposure, including various limited sampling strategies of the AUC (lssAUC) in the early postdose period, or alternative single-point nontrough samples, such as a 2-hour postdose sample (C2). The present study has reviewed a series of consecutive renal transplant recipients over 18 months where CsA was the primary immunosuppressant. The lssAUC performed at around day 7 posttransplantation included drawing blood at 0, 2, and 4 hours postdose, giving AUC(0-4). The aim of this study was to review the occurrence of acute biopsy-proven rejection in the first month and consider which of (simultaneously measured) C0, C2 or AUC(0-4) was a better early indicator of this adverse outcome. The result was best described by comparing the data from rejectors (n = 13) and nonrejectors (n = 42) for these 3 indices of CsA exposure (i.e., C0, C2 or AUC(0-4)). There was no evidence that C0 predicted the likelihood of such adverse clinical outcomes. In contrast, rejectors tended to have lower mean C2 CsA concentrations, and the incidence of rejection was 0.0 when C2 exceeded 1200 microg/L (n = 10). While the data are limited in the higher C2 CsA concentration range, it is nevertheless consistent with more recent recommendations suggesting that the CsA at C2 should target 1700 microg/L in this first month posttransplantation. As 64% of the patients were also receiving a CsA-sparing agent (diltiazem [DTZ]), the relationships were also investigated to determine whether any affect of concomitant DTZ therapy could be demonstrated. However, in this small sample, no significant affect of DTZ was seen.