Purpose: Scarce information is available on the brain penetration of temozolomide (TMZ), although this novel methylating agent is mainly used for the treatment of malignant brain tumors. The purpose was to assess TMZ pharmacokinetics in plasma and cerebrospinal fluid (CSF) along with its inter-individual variability, to characterize covariates and to explore relationships between systemic or cerebral drug exposure and clinical outcomes. Experimental Design: TMZ levels were measured by high-performance liquid chromatography in plasma and CSF samples from 35 patients with newly diagnosed or recurrent malignant gliomas. The population pharmacokinetic analysis was performed with nonlinear mixed-effect modeling software. Drug exposure, defined by the area under the concentration-time curve (AUC) in plasma and CSF, was estimated for each patient and correlated with toxicity, survival, and progression-free survival. Results: A three-compartment model with first-order absorption and transfer rates between plasma and CSF described the data appropriately. Oral clearance was 10 liter/h; volume of distribution (V_D), 30.3 liters; absorption constant rate, 5.8 h⁻¹; elimination half-time, 2.1 h; transfer rate from plasma to CSF (K_plasma→CSF), 7.2 × 10⁻⁴h⁻¹ and the backwards rate, 0.76 h⁻¹. Body surface area significantly influenced both clearance and V_D, and clearance was sex dependent. The AUC_CSF corresponded to 20% of the AUC_plasma. A trend toward an increased K_plasma→CSF of 15% was observed in case of concomitant radiochemotherapy. No significant correlations between AUC in plasma or CSF and toxicity, survival, or progression-free survival were apparent after deduction of dose-effect. Conclusions: This is the first human pharmacokinetic study on TMZ to quantify CSF penetration. The AUC_CSF/AUC_plasma ratio was 20%. Systemic or cerebral exposures are not better predictors than the cumulative dose alone for both efficacy and safety.

Objective: The reverse transcriptase inhibitor efavirenz is currently used at a fixed dose of 600 mg/d. However, dosage individualization based on plasma concentration monitoring might be indicated. This study aimed to assess the efavirenz pharmacokinetic profile and interpatient versus intrapatient variability in patients who are positive for human immunodeficiency virus, to explore the relationship between drug exposure, efficacy, and central nervous system toxicity and to build up a Bayesian approach for dosage adaptation.Methods: The population pharmacokinetic analysis was performed by use of NONMEM based on plasma samples from a cohort of unselected patients receiving efavirenz. With the use of a 1‐compartment model with first‐order absorption, the influence of demographic and clinical characteristics on oral clearance and oral volume of distribution was examined. The average drug exposure during 1 dosing interval was estimated for each patient and correlated with markers of efficacy and toxicity. The population kinetic parameters and the variabilities were integrated into a Bayesian equation for dosage adaptation based on a single plasma sample.Results: Data from 235 patients with a total of 719 efavirenz concentrations were collected. Oral clearance was 9.4 L/h, oral volume of distribution was 252 L, and the absorption rate constant was 0.3 h⁻¹. Neither the demographic covariates evaluated nor the comedications showed a clinically significant influence on efavirenz pharmacokinetics. A large interpatient variability was found to affect efavirenz relative bioavailability (coefficient of variation, 54.6%), whereas the intrapatient variability was small (coefficient of variation, 26%). An inverse correlation between average drug exposure and viral load and a trend with central nervous system toxicity were detected. This enabled the derivation of a dosing adaptation strategy suitable to bring the average concentration into a therapeutic target from 1000 to 4000 μg/L to optimize viral load suppression and to minimize central nervous system toxicity.Conclusions: 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.Clinical Pharmacology & Therapeutics (2003) 73, 20–30; doi: 10.1067/mcp.2003.22

The importance of sex and gender as modulators of disease biology and treatment outcomes is well known in other disciplines of medicine, such as cardiology, but remains an undervalued issue in oncology. Considering the increasing evidence for their relevance, European Society for Medical Oncology decided to address this topic and organized a multidisciplinary workshop in Lausanne, Switzerland, on 30 November and 1 December 2018. Twenty invited faculty members and 40 selected physicians/scientists participated. Relevant content was presented by faculty members on the basis of a literature review conducted by each speaker. Following a moderated consensus session, the final consensus statements are reported here. Clinically relevant sex differences include tumour biology, immune system activity, body composition and drug disposition and effects. The main differences between male and female cells are sex chromosomes and the level of sexual hormones they are exposed to. They influence both local and systemic determinants of carcinogenesis. Their effect on carcinogenesis in non-reproductive organs is largely unknown. Recent evidence also suggests differences in tumour biology and molecular markers. Regarding body composition, the difference in metabolically active, fat-free body mass is one of the most prominent: in a man and a woman of equal weight and height, it accounts for 80% of the man's and 65% of the woman's body mass, and is not taken into account in body-surface area based dosing of chemotherapy. Sex differences in cancer biology and treatment deserve more attention and systematic investigation. Interventional clinical trials evaluating sex-specific dosing regimens are necessary to improve the balance between efficacy and toxicity for drugs with significant pharmacokinetic differences. Especially in diseases or disease subgroups with significant differences in epidemiology or outcomes, men and women with non-sex-related cancers should be considered as biologically distinct groups of patients, for whom specific treatment approaches merit consideration.

Background. Recommended oral voriconazole (VRC) doses are lower than intravenous doses. Because plasma concentrations impact efficacy and safety of therapy, optimizing individual drug exposure may improve these outcomes. Methods. A population pharmacokinetic analysis (NONMEM) was performed on 505 plasma concentration measurements involving 55 patients with invasive mycoses who received recommended VRC doses. Results. A 1-compartment model with first-order absorption and elimination best fitted the data. VRC clearance was 5.2 L/h, the volume of distribution was 92 L, the absorption rate constant was 1.1 hour⁻¹, and oral bioavailability was 0.63. Severe cholestasis decreased VRC elimination by 52%. A large interpatient variability was observed on clearance (coefficient of variation [CV], 40%) and bioavailability (CV 84%), and an interoccasion variability was observed on bioavailability (CV, 93%). Lack of response to therapy occurred in 12 of 55 patients (22%), and grade 3 neurotoxicity occurred in 5 of 55 patients (9%). A logistic multivariate regression analysis revealed an independent association between VRC trough concentrations and probability of response or neurotoxicity by identifying a therapeutic range of 1.5 mg/L (>85% probability of response) to 4.5 mg/L (<15% probability of neurotoxicity). Population-based simulations with the recommended 200 mg oral or 300 mg intravenous twice-daily regimens predicted probabilities of 49% and 87%, respectively, for achievement of 1.5 mg/L and of 8% and 37%, respectively, for achievement of 4.5 mg/L. With 300–400 mg twice-daily oral doses and 200–300 mg twice-daily intravenous doses, the predicted probabilities of achieving the lower target concentration were 68%–78% for the oral regimen and 70%–87% for the intravenous regimen, and the predicted probabilities of achieving the upper target concentration were 19%–29% for the oral regimen and 18%–37% for the intravenous regimen. Conclusions. Higher oral than intravenous VRC doses, followed by individualized adjustments based on measured plasma concentrations, improve achievement of the therapeutic target that maximizes the probability of therapeutic response and minimizes the probability of neurotoxicity. These findings challenge dose recommendations for VRC.

Aims: The 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 α₁‐acid glycoprotein concentrations.Methods: A 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.Results: A 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 α₁‐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.Conclusion: Because of the high pharmacokinetic variability of imatinib and the reported relationships between its plasma concentration and efficacy and toxicity, the usefulness of therapeutic drug monitoring as an aid to optimizing therapy should be further investigated. Ideally, such an approach should take account of either circulating α₁‐acid glycoprotein concentrations or free imatinib concentrations.