Imatinib, sunitinib and pazopanib:From flat-fixed dosing towards a pharmacokinetically guided personalized dose

Tyrosine kinase inhibitors (TKIs) are anti-cancer drugs that target tyrosine kinases, enzymes that are involved in multiple cellular processes. Currently, multiple oral TKIs have been introduced in the treatment of solid tumours, all administered in a fixed dose, although large interpatient pharmacokinetic (PK) variability is described. For imatinib, sunitinib and pazopanib exposure-treatment outcome (efficacy and toxicity) relationships have been established and therapeutic windows have been defined, therefore dose optimization based on the measured blood concentration, called therapeutic drug monitoring (TDM), can be valuable in increasing efficacy and reducing the toxicity of these drugs. In this review, an overview of the current knowledge on TDM guided individualized dosing of imatinib, sunitinib and pazopanib for the treatment of solid tumours is presented. We summarize preclinical and clinical data that have defined thresholds for efficacy and toxicity. Furthermore, PK models and factors that influence the PK of these drugs which partly explain the interpatient PK variability are summarized. Finally, pharmacological interventions that have been performed to optimize plasma concentrations are described. Based on current literature, we advise which methods should be used to optimize exposure to imatinib, sunitinib and pazopanib

Impact of CYP3A4*22 on Pazopanib Pharmacokinetics in Cancer Patients

Background and Objective: As pazopanib plasma trough concentrations are correlated with treatment outcome, we explored whether single nucleotide polymorphisms in the elimination pathway of pazopanib affect systemic pazopanib concentrations. Methods: The decreased function alleles CYP3A4 15389 C > T (*22), ABCB1 3435 C >T, ABCG2 421 C >A, and ABCG2 34G >A were analyzed within a recently developed population-pharmacokinetic model. Results: Incorporation of CYP3A4*22 in the model resulted in a 35% lower clearance for variant carriers (0.18 vs. 0.27 L/h; difference in objective function value: − 9.7; p < 0.005). Simulated median trough concentrations of cancer patients with CYP3A4*22 with 600 mg once daily or 800 mg once daily were 31 and 35 mg/L, respectively. The simulated trough concentrations for the population excluding the CYP3A4*22 carriers after 600 mg once daily or 800 mg once daily were 18 and 20 mg/L, respectively. Conclusion: This analysis shows that CYP3A4*22 heterozygotes have a substantial lower pazopanib clearance and that dose adjustments based on CYP3A4*22 status could be considered

Marginal increase of sunitinib exposure by grapefruit juice

Clinical Oncolog

Use of incretin agents and risk of pancreatic cancer: a poputation-based cohort study

OBJECTIVE: To determine the association between the use of incretin agents and the risk of pancreatic Cancer. Incretins (dipeptidyl peptidase 4 [DPP-4] inhibitors and glucaconlike peptide 1 [GLP-1] receptor analogues] are effective new agents for the treatment of type 2 diabetes mellitus (T2DM). Incretins have been associated with pancreatic Cancer, but evidence is limited and conflicting. DESIGN AND METHODS: A retrospective population-based cohort study was conducted using data from the UK Clinical Practice Research Datalink (CPRD, 2007-2012). 182.428 adult patients with at least one non-insulin antidiabetic drug INIAD] prescription were matched to non-diabetic controls. Multivariable Cox proportional hazard ratios (HRa) and 95% confidence intervals (CI95) were used to estimate the risk of pancreatic Cancer in incretin users (N = 28,3701 as compared to controls and to other NIAD users. Adjustments were made for lifestyle, disease and drug history. In a sensitivity analysis, a new user design was used. RESULTS: The main duration of follow up was 4.1 years for incretin users. Current NIAD use was associated with a 4-fold increased risk of pancreatic Cancer and this risk almost doubled among current incretin users as compared to controls. Incretin use was not associated with pancreatic Cancer when compared to diabetic controls (HRa 1.36; CI95 0.94-1.961. However, the new user design did show an association between incretin use and pancreatic Cancer. CONCLUSION: Incretin use was not associated with pancreatic Cancer after adjustment for the severity of the underlying T2DM. The presence of confounding by disease severity and the lack of duration of use relationship do not support a causal explanation for the association between incretin agents and pancreatic Cancer

Dose Reduction May Jeopardize Efficacy of Abiraterone Acetate

status: publishe

Exposure to Docetaxel in the Elderly Patient Population: a Population Pharmacokinetic Study

BACKGROUND: Docetaxel is commonly used in elderly patients, who are frequently diagnosed with prostate cancer. Although previous studies revealed no clinically relevant impact of older age on docetaxel pharmacokinetics (PK), this may be masked by indication. Metastatic castration-resistant prostate cancer (mCRPC) patients were reported to have approximately two-times lower systemic exposure compared to patients with other solid tumors. This study assessed the impact of older age on docetaxel PK, also considering the effect of indication on docetaxel PK. METHODS: Prospectively collected docetaxel PK data from patients aged ≥70 was pooled with PK data from an earlier published multicenter study. A 3-compartment population PK model, including multiple covariates, was used to describe docetaxel plasma concentration-time data. We added the effect of prostate cancer (mCRPC and metastatic hormone-sensitive prostate cancer (mHSPC)) on clearance to this model. Hereafter, we evaluated the additional impact of older age on docetaxel clearance, using a significance threshold of p < 0.005. RESULTS: Docetaxel plasma concentration-time data from 157 patients were analyzed. Median age in the total cohort was 67 years (range 31-87), with 49% of the total cohort aged ≥70. The impact of age on docetaxel clearance was statistically significant (p < 0.005). For a typical patient, a 10-year and 20-year increase of age led to a reduction in clearance of 17% and 34%, respectively. CONCLUSION: In this cohort study, age significantly and independently affected docetaxel clearance, showing lower docetaxel clearance in elderly patients. In our cohort, mCRPC and mHSPC patients both had higher clearance than patients with other solid tumors

The Effect of Tamoxifen Dose Increment in Patients With Impaired CYP2D6 Activity

The effect of tamoxifen dose elevation on endoxifen serum concentration was investigated in patients with reduced CYP2D6 activity resulting from genetic variation and/or CYP2D6 inhibitor use. Additionally, baseline differences in endoxifen concentrations between the different CYP2D6 phenotypes were studied. Patients, treated with tamoxifen 20 mg once daily (QD) for at least 4 weeks, were classified as phenotypic extensive (EM), intermediate (IM), or poor (PM) metabolizer based on their genotype and comedication. In patients with an IM or PM phenotype, the tamoxifen dose was increased to 40 mg QD for 4 weeks. Tamoxifen, 4-OH-tamoxifen, N-desmethyltamoxifen, and endoxifen serum concentrations were measured at baseline and 4 weeks after the dose increment. Side effects of tamoxifen were assessed using the validated Functional Assessment of Cancer Therapy-Endocrine Symptom subscale (FACT-ESS-19). The median baseline endoxifen concentration differed between EMs (11.4 mcg/L: n = 19), IMs (8.3 mcg/L: n = 16), and PMs (4.0 mcg/L: n = 7), P = 0.040. Tamoxifen dose elevation significantly increased the median endoxifen concentrations in 12 IMs from 9.5 to 17.4 mcg/L (P < 0.001) and in 4 PMs from 3.8 to 7.8 mcg/L (P = 0.001), without influencing median FACT-ESS-19 scores. Raising the tamoxifen dose to 40 mg QD significantly increased endoxifen concentrations in IMs and PMs without increasing side effects. The tamoxifen dose increment in PMs was insufficient to reach endoxifen concentrations equal to those observed in EMs. Future studies will clarify the direct effect of endoxifen exposure on tamoxifen efficacy and may reveal a threshold endoxifen concentration that is critical for its efficac