AimsThere are limited pharmacokinetic data on the use of irinotecan in patients with reduced glomerular filtration rate (GFR) and no haemodialysis. In this case report, we present 2 cases and... Show moreAimsThere are limited pharmacokinetic data on the use of irinotecan in patients with reduced glomerular filtration rate (GFR) and no haemodialysis. In this case report, we present 2 cases and review the current literature. MethodsThe dose of irinotecan in both patients was reduced pre-emptively due to reduced GFR. The first patient had her irinotecan dose reduced to 50%, but was nevertheless admitted to hospital because of irinotecan-induced toxicity, including gastrointestinal toxicity and neutropenic fever. The dose was reduced further to 40% for the second cycle; however, the patient was again admitted to the hospital, and irinotecan was stopped indefinitely. The second patient also had his irinotecan dose reduced to 50% and was admitted to the emergency department for gastrointestinal toxicity after the first cycle. However, irinotecan could be administered in the same dose in later cycles. ResultsThe area under the curve to infinity of irinotecan and SN-38 in the first patient were comparable to those of an individual receiving 100% dose intensity. The area under the curve to infinity of irinotecan and SN-38 in patient 2 in both cycles were slightly less than reference values. Furthermore, clearance values of irinotecan and SN-38 in our patients were comparable to those without renal impairment. ConclusionOur case report suggests that reduced GFR may not significantly affect the clearance of irinotecan and SN-38, but can still result in clinical toxicity. Reduced initial dosing seems indicated in this patient population. Further research is needed to fully understand the relationship between reduced GFR, pharmacokinetics, and toxicity of irinotecan and SN-38. Show less
IntroductionA genetic variant explaining a part of the exposure of many kinase inhibitors (KIs) is the single nucleotide polymorphism (SNP) CYP3A4*22, resulting in less CYP3A4 enzyme activity. The... Show moreIntroductionA genetic variant explaining a part of the exposure of many kinase inhibitors (KIs) is the single nucleotide polymorphism (SNP) CYP3A4*22, resulting in less CYP3A4 enzyme activity. The primary aim of this study was to investigate if the systemic exposure is non-inferior after a dose reduction of KIs metabolized by CYP3A4 in CYP3A4*22 carriers compared to patients without this SNP (i.e., wildtype patients) receiving the standard dose.MethodsIn this multicenter, prospective, non-inferiority study, patients were screened for the presence of CYP3A4*22. Patients with the CYP3A4*22 SNP received a 20-33% dose reduction. At steady state, a pharmacokinetic (PK) analysis was performed and compared to the PK results from wildtype patients treated with the registered dose using a two-stage individual patient data meta-analysis approach.ResultsIn total, 207 patients were included in the final analysis. The CYP3A4*22 SNP was found in 16% of the patients in the final analysis (n = 34). Most of the included patients received imatinib (37%) or pazopanib (22%) treatment. The overall geometric mean ratio (GMR) comparing the exposure of the CYP3A4*22 carriers to the exposure of the wildtype CYP3A4 patients was 0.89 (90% confidence interval: 0.77-1.03).ConclusionNon-inferiority could not be proven for dose reduction of KIs metabolized by CYP3A4 in CYP3A4*22 carriers compared to the registered dose in wildtype patients. Therefore, an up-front dose reduction based upon the CYP3A4*22 SNP for all KIs does not seem an eligible new way of personalized therapy. Show less
Background Central nervous system (CNS) metastases are present in approximately 40% of patients with metastatic epidermal growth factor receptor-mutated (EGFRm+) non-small cell lung cancer (NSCLC).... Show moreBackground Central nervous system (CNS) metastases are present in approximately 40% of patients with metastatic epidermal growth factor receptor-mutated (EGFRm+) non-small cell lung cancer (NSCLC). The EGFR-tyrosine kinase inhibitor osimertinib is a substrate of transporters ABCB1 and ABCG2 and metabolized by CYP3A4. We investigated relationships between single nucleotide polymorphisms (SNPs) ABCB1 3435C>T, ABCG2 421C>A and 34G>A, and CYP3A4*22 and CNS treatment efficacy of osimertinib in EGFRm+ NSCLC patients. Methods Patients who started treatment with osimertinib for EGFRm+ NSCLC between November 2014 and June 2021 were included in this retrospective observational multicentre cohort study. For patients with baseline CNS metastases, the primary endpoint was CNS progression-free survival (CNS-PFS; time from osimertinib start until CNS disease progression or death). For patients with no or unknown baseline CNS metastases, the primary endpoint was CNS disease-free survival (CNS-DFS; time from osimertinib start until occurrence of new CNS metastases). Relationships between SNPs and baseline characteristics with CNS-PFS and CNS-DFS were studied with competing-risks survival analysis. Secondary endpoints were relationships between SNPs and PFS, overall survival, severe toxicity, and osimertinib pharmacokinetics. Findings From 572 included patients, 201 had baseline CNS metastases. No SNP was associated with CNS-PFS. Genotype ABCG2 34GA/AA and/or ABCB1 3435CC -present in 35% of patients- was significantly associated with decreased CNS-DFS (hazard ratio 0.28; 95% CI 0.11-0.73; p = 0.009) in the multivariate analysis. This remained significant after applying a Bonferroni correction and internal validation through bootstrapping. ABCG2 421CA/ AA was related to more severe toxicity (27.0% versus 16.5%; p = 0.010). Interpretation ABCG2 34G>A and ABCB1 3435C>T are predictors for developing new CNS metastases during osi-mertinib treatment, probably because of diminished drug levels in the CNS. ABCG2 421C>A was significantly related with the incidence of severe toxicity. Pre-emptive genotyping for these SNPs could individualize osimertinib therapy. Addition of ABCG2 inhibitors for patients without ABCG2 34G>A should be studied further, to prevent new CNS metastases during osimertinib treatment. Show less
Background: Oral targeted therapies show a high pharmacokinetic (PK) interpatient variability. Even though exposure has been positively correlated with efficacy for many of these drugs, these are... Show moreBackground: Oral targeted therapies show a high pharmacokinetic (PK) interpatient variability. Even though exposure has been positively correlated with efficacy for many of these drugs, these are still dosed using a one-size-fits-all approach. Consequently, individuals have a high probability to be either underexposed or overexposed, potentially leading to suboptimal outcomes. Therapeutic drug monitoring, which is personalized dosing based on measured systemic drug concentrations, could address these problems.Patients and methods: Patients were enrolled in this prospective multicenter study (www.trialregister.nl; NL6695) if they started treatment with one of the 24 participating oral targeted therapies. Primary outcome was to halve the proportion of underexposed patients, compared with historical data. PK sampling was carried out after 4, 8 and 12 weeks, and every 12 weeks thereafter. In case of Cmin below the predefined target and manageable toxicity, a pharmacokinetically guided intervention was proposed (i.e. checking compliance and drugedrug interactions, concomitant intake with food, splitting intake moments or dose increments).Results: In total, 600 patients were included of whom 426 patients are assessable for the primary outcome and 552 patients had >= 1 PK sample(s) available and were therefore assessable for the overall analyses. Pharmacokinetically guided dosing reduced the proportion of underexposed patients at the third PK measurement by 39.0% (95% confidence interval 28.0% to 49.0%) compared with historical data. At the third PK measurement, 110 out of 426 patients (25.8%) had a low exposure. In total, 294 patients (53.3%) had >= 1 PK sample(s) below the preset target at a certain time point during treatment. In 166 of these patients (56.5%), pharmacokinetically guided interventions were carried out, which were successful in 113 out of 152 assessable patients (74.3%).Conclusions: Pharmacokinetically guided dose optimization of oral targeted therapies was feasible in clinical practice and reduced the proportion of underexposed patients considerably. Show less
Aim: To determine the safety, feasibility, pharmacokinetics, and cost of UGT1A1 genotype-guided dosing of irinotecan.Patients and methods: In this prospective, multicentre, non-randomised study,... Show moreAim: To determine the safety, feasibility, pharmacokinetics, and cost of UGT1A1 genotype-guided dosing of irinotecan.Patients and methods: In this prospective, multicentre, non-randomised study, patients intended for treatment with irinotecan were pre-therapeutically genotyped for UGT1A1*28 and UGT1A1)93. Homozygous variant carriers (UGT1A1 poor metabolisers; PMs) received an initial 30% dose reduction. The primary endpoint was incidence of febrile neutropenia in the first two cycles of treatment. Toxicity in UGT1A1 PMs was compared to a historical cohort of UGT1A1 PMs treated with full dose therapy, and to UGT1A1 non-PMs treated with full dose therapy in the current study. Secondary endpoints were pharmacokinetics, feasi- bility, and costs.Results: Of the 350 evaluable patients, 31 (8.9%) patients were UGT1A1 PM and received a median 30% dose reduction. The incidence of febrile neutropenia in this group was 6.5% compared to 24% in historical UGT1A1 PMs (P = 0.04) and was comparable to the incidence in UGT1A1 non-PMs treated with full dose therapy. Systemic exposure of SN-38 of reduced dosing in UGT1A1 PMs was still slightly higher compared to a standard-dosed irinotecan patient cohort (difference: thorn 32%). Cost analysis showed that genotype-guided dosing was cost-saving with a cost reduction of V183 per patient.Conclusion: UGT1A1 genotype-guided dosing significantly reduces the incidence of febrile neutropenia in UGT1A1 PM patients treated with irinotecan, results in a therapeutically effec- tive systemic drug exposure, and is cost-saving. Therefore, UGT1A1 genotype-guided dosing of irinotecan should be considered standard of care in order to improve individual patient safety. (C) 2022 The Authors. Published by Elsevier Ltd. Show less
Steendam, C.M.J.; Peric, R.; Walree, N.C. van; Youssef, M.; Schramel, F.M.N.H.; Brocken, P.; ... ; NVALT Study Grp 2021
Background: Earlier preclinical and phase II research showed enhanced effect of docetaxel plus intercalated erlotinib. The NVALT-18 phase III study was designed to compare docetaxel with docetaxel... Show moreBackground: Earlier preclinical and phase II research showed enhanced effect of docetaxel plus intercalated erlotinib. The NVALT-18 phase III study was designed to compare docetaxel with docetaxel plus intercalated erlotinib in relapsed metastasized non-squamous (NSQ) non-small cell lung cancer (NSCLC).Methods: Patients with relapsed Epidermal Growth Factor Receptor (EGFR) wild type (WT) NSQ-NSCLC were randomized 1:1 to docetaxel 75 mg/m(2) intravenously on day 1 every 21 days (control), or docetaxel 75 mg/m(2) intravenously on day 1 plus erlotinib 150 mg/day orally on day 2-16 every 21 days (experimental arm). Progression free survival (PFS) was the primary endpoint, secondary objectives were duration of response, overall survival (OS) and toxicity.Results: Between October 2016 and April 2018 a total of 45 patients were randomized and received treatment in the control (N = 23) or experimental arm (N = 22), the study was stopped due to slow accrual. Median PFS was 4.0 months (95% CI: 1.5-7.1) versus 1.9 months (95% CI 1.4-3.5), p = 0.01 respectively; adjusted hazard ratio (HR) 2.51 (95% CI: 1.16-5.43). Corresponding median OS was 10.6 months (95% CI: 7.0-8.6) versus 4.7 months (95% CI: 3.2-8.6), p = 0.004, with an adjusted HR of 3.67 (95% CI: 1.46-9.27). Toxicity was higher with combination therapy, with toxicity >= CTCAE grade 3 in N = 6 (26%) in the control arm and N = 17 (77%) in the experimental arm (p < 0.001), mainly consisting of gastrointestinal symptoms and leukopenia.Conclusions: Our study shows detrimental effects of docetaxel plus intercalated erlotinib, and strongly discourages further exploration of this combination in clinical practice. Show less
Background Many cancer patients use additional herbs or supplements in combination with their anti-cancer therapy. Green tea-active ingredient epigallocatechin-3-gallate (EGCG)-is one of the most... Show moreBackground Many cancer patients use additional herbs or supplements in combination with their anti-cancer therapy. Green tea-active ingredient epigallocatechin-3-gallate (EGCG)-is one of the most commonly used dietary supplements among breast cancer patients. EGCG may alter the metabolism of tamoxifen. Therefore, the aim of this study was to investigate the influence of green tea supplements on the pharmacokinetics of endoxifen; the most relevant active metabolite of tamoxifen. Methods In this single-center, randomized cross-over trial, effects of green tea capsules on endoxifen levels were evaluated. Patients treated with tamoxifen for at least 3 months were eligible for this study. After inclusion, patients were consecutively treated with tamoxifen monotherapy for 28 days and in combination with green tea supplements (1 g twice daily; containing 300 mg EGCG) for 14 days (or vice versa). Blood samples were collected on the last day of monotherapy or combination therapy. Area under the curve (AUC(0-24h)), maximum concentration (C-max) and minimum concentration (C-trough) were obtained from individual plasma concentration-time curves. Results No difference was found in geometric mean endoxifen AUC(0-24h)in the period with green tea versus tamoxifen monotherapy (- 0.4%; 95% CI - 8.6 to 8.5%;p = 0.92). Furthermore, no differences inC(max)(- 2.8%; - 10.6 to 5.6%;p = 0.47) norC(trough)(1.2%; - 7.3 to 10.5%;p = 0.77) were found. Moreover, no severe toxicity was reported during the whole study period. Conclusions This study demonstrated the absence of a pharmacokinetic interaction between green tea supplements and tamoxifen. Therefore, the use of green tea by patients with tamoxifen does not have to be discouraged. Show less
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... Show moreTyrosine 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. Show less
Background: Oral anticancer drugs show a high interpatient variability in pharmacokinetics (PK), leading to large differences in drug exposure. For many of these drugs, exposure has been linked to... Show moreBackground: Oral anticancer drugs show a high interpatient variability in pharmacokinetics (PK), leading to large differences in drug exposure. For many of these drugs, exposure has been linked to efficacy and toxicity. Despite this knowledge, these drugs are still administered in a one-size-fits-all approach. Consequently, individual patients have a high probability to be either underdosed, which can lead to decreased antitumor efficacy, or overdosed, which could potentially result in increased toxicity. Therapeutic drug monitoring (TDM), personalized dosing based on measured drug levels, could be used to circumvent underdosing and overdosing and thereby optimize treatment outcomes.Methods: In this prospective clinical study (www.trialregister.nl; NL6695), the feasibility, tolerability, and efficacy of TDM of oral anticancer drugs will be evaluated. In total, at least 600 patients will be included for (at least) 23 different compounds. Patients starting regular treatment with one of these compounds at the approved standard dose can be included. PK sampling will be performed at 4, 8, and 12 weeks after the start of treatment and every 12 weeks thereafter. Drug concentrations will be measured, and trough concentrations (C-min) will be calculated. In cases where C-min, falls below the predefined target and acceptable toxicity, a PK-guided intervention will be recommended. This could include emphasizing compliance, adapting concomitant medication (due to drug-drug interactions), instructing to take the drug concomitant with food, splitting intake moments, or recommending a dose increase.Discussion: Despite a strong rationale for the use of TDM for oral anticancer drugs, this is currently not yet widely adopted in routine patient care. This prospective study will be a valuable contribution to demonstrate the additional value of dose optimization on treatment outcome for these drugs. Show less
Bins, S.; Huitema, A.D.R.; Laven, P.; Bouazzaoui, S. el; Yu, H.X.; Erp, N. van; ... ; Koolen, S.L.W. 2019
Background and ObjectiveAs pazopanib plasma trough concentrations are correlated with treatment outcome, we explored whether single nucleotide polymorphisms in the elimination pathway of pazopanib... Show moreBackground and ObjectiveAs 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.MethodsThe 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.ResultsIncorporation 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 600mg once daily or 800mg once daily were 31 and 35mg/L, respectively. The simulated trough concentrations for the population excluding the CYP3A4*22 carriers after 600mg once daily or 800mg once daily were 18 and 20mg/L, respectively.ConclusionThis analysis shows that CYP3A4*22 heterozygotes have a substantial lower pazopanib clearance and that dose adjustments based on CYP3A4*22 status could be considered. Show less
Kuip, E.J.M.; Zandvliet, M.L.; Koolen, S.L.W.; Mathijssen, R.H.J.; Rijt, C.C.D. van der 2017
