Treatment failure and CNS side-effects are associated with low and high efavirenz plasma levels, respectively. The important inter-individual variability in efavirenz levels strongly argues for dose adjustment on the basis of therapeutic drug monitoring to optimize treatment.

CYP2B6 516TT was associated with greater plasma and intracellular exposure to EFV, and greater plasma exposure to NVP. Intracellular drug concentration, and CYP2B6 genotype were predictors of EFV neuropsychological toxicity. CYP2B6 genotyping may be useful to complement an individualization strategy based on plasma drug determinations to increase the safety and tolerability of EFV.

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The high interpatient and low intrapatient variability values, as well as the potential relationship with markers of efficacy and toxicity, support the therapeutic drug monitoring of efavirenz. However, further evaluation is needed before individualization of an efavirenz dosage regimen based on routine drug level monitoring should be recommended for optimal patient management.

AimsThe aims of this observational study were to assess the variability in imatinib pharmacokinetics and to explore the relationship between its disposition and various biological covariates, especially plasma α 1 -acid glycoprotein concentrations. MethodsA population pharmacokinetic analysis was performed using NONMEM based on 321 plasma samples from 59 patients with either chronic myeloid leukaemia or gastrointestinal stromal tumours. The influence of covariates on oral clearance and volume of distribution was examined. Furthermore, the in vivo intracellular pharmacokinetics of imatinib was explored in five patients. ResultsA one-compartment model with first-order absorption appropriately described the data, giving a mean ( ± SEM) oral clearance of 14.3 l h − 1 ( ± 1.0) and a volume of distribution of 347 l ( ± 62). Oral clearance was influenced by body weight, age, sex and disease diagnosis. A large proportion of the interindividual variability (36% of clearance and 63% of volume of distribution) remained unexplained by these demographic covariates. Plasma α 1 -acid glycoprotein concentrations had a marked influence on total imatinib concentrations. Moreover, we observed an intra/extracellular ratio of 8, suggesting substantial uptake of the drug into the target cells. ConclusionBecause of the high pharmacokinetic variability of imatinib and the repor ted relationships between its plasma concentration and efficacy and toxicity, the usefulness of therapeutic drug monitoring as an aid to optimizing therapy should be fur ther investigated. Ideally, such an approach should take account of either circulating α 1 -acid glycoprotein concentrations or free imatinib concentrations.