Monoclonal antibodies (mAbs) have been used in the treatment of various diseases for over 20 years and combine high specificity with generally low toxicity. Their pharmacokinetic properties differ ...markedly from those of non-antibody-type drugs, and these properties can have important clinical implications. mAbs are administered intravenously, intramuscularly or subcutaneously. Oral administration is precluded by the molecular size, hydrophilicity and gastric degradation of mAbs. Distribution into tissue is slow because of the molecular size of mAbs, and volumes of distribution are generally low. mAbs are metabolized to peptides and amino acids in several tissues, by circulating phagocytic cells or by their target antigen-containing cells. Antibodies and endogenous immunoglobulins are protected from degradation by binding to protective receptors (the neonatal Fc-receptor FcRn), which explains their long elimination half-lives (up to 4 weeks). Population pharmacokinetic analyses have been applied in assessing covariates in the disposition of mAbs. Both linear and nonlinear elimination have been reported for mAbs, which is probably caused by target-mediated disposition. Possible factors influencing elimination of mAbs include the amount of the target antigen, immune reactions to the antibody and patient demographics. Bodyweight and/or body surface area are generally related to clearance of mAbs, but clinical relevance is often low. Metabolic drug-drug interactions are rare for mAbs. Exposure-response relationships have been described for some mAbs. In conclusion, the parenteral administration, slow tissue distribution and long elimination half-life are the most pronounced clinical pharmacokinetic characteristics of mAbs.
The inhibition of poly(adenosine diphosphate ADP-ribose) polymerase (PARP) is a potential synthetic lethal therapeutic strategy for the treatment of cancers with specific DNA-repair defects, ...including those arising in carriers of a BRCA1 or BRCA2 mutation. We conducted a clinical evaluation in humans of olaparib (AZD2281), a novel, potent, orally active PARP inhibitor.
This was a phase 1 trial that included the analysis of pharmacokinetic and pharmacodynamic characteristics of olaparib. Selection was aimed at having a study population enriched in carriers of a BRCA1 or BRCA2 mutation.
We enrolled and treated 60 patients; 22 were carriers of a BRCA1 or BRCA2 mutation and 1 had a strong family history of BRCA-associated cancer but declined to undergo mutational testing. The olaparib dose and schedule were increased from 10 mg daily for 2 of every 3 weeks to 600 mg twice daily continuously. Reversible dose-limiting toxicity was seen in one of eight patients receiving 400 mg twice daily (grade 3 mood alteration and fatigue) and two of five patients receiving 600 mg twice daily (grade 4 thrombocytopenia and grade 3 somnolence). This led us to enroll another cohort, consisting only of carriers of a BRCA1 or BRCA2 mutation, to receive olaparib at a dose of 200 mg twice daily. Other adverse effects included mild gastrointestinal symptoms. There was no obvious increase in adverse effects seen in the mutation carriers. Pharmacokinetic data indicated rapid absorption and elimination; pharmacodynamic studies confirmed PARP inhibition in surrogate samples (of peripheral-blood mononuclear cells and plucked eyebrow-hair follicles) and tumor tissue. Objective antitumor activity was reported only in mutation carriers, all of whom had ovarian, breast, or prostate cancer and had received multiple treatment regimens.
Olaparib has few of the adverse effects of conventional chemotherapy, inhibits PARP, and has antitumor activity in cancer associated with the BRCA1 or BRCA2 mutation. (ClinicalTrials.gov number, NCT00516373.)
Wee1 is a protein kinase that regulates the G
checkpoint and prevents entry into mitosis in response to DNA damage. Cyclin-dependent kinases (CDK) are a family of 14 serine/threonine protein kinases ...that coordinate the progression through the cell cycle. The Cdc2/cyclin B complex controls the progression from G
into mitosis. There are two mechanisms by which the G
checkpoint is initiated in response to DNA damage: phosphorylation of Cdc25c by CHK1 and of the Wee1 kinase, which phosphorylates Cdc2. Blockade at the G
checkpoint is especially important for p53-mutant cells because these tumors mainly rely on DNA repair at the G
checkpoint. AZD1775 (formerly MK-1775) is a small-molecule, pyrazol-pyrimidine derivative and potent and ATP-competitive specific inhibitor of the Wee1 kinase. Several preclinical and clinical studies demonstrated encouraging antitumor effects with manageable side effects of the combination of Wee1 inhibition and DNA-damaging agents. Promising combination schedules are being investigated at the moment, for example, combining PARP inhibition and Wee1 inhibition. Also, a weekly schedule with carboplatin and AZD1775 warrants investigation aimed at further improving the antitumor effect.
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There is accumulating evidence for potential benefits of therapeutic drug monitoring (TDM) in the treatment of cancer with tyrosine kinase inhibitors (TKIs). Relationships between exposure and ...response (efficacy/toxicity) have been established for several TKIs. For example, the pharmacokinetic targets for efficacy of imatinib, sunitinib and pazopanib have been defined as trough plasma concentrations (Ctrough) of >1,000, >50 and >20,000 ng/mL for selected indications, respectively. Dose adjustment based on pharmacokinetic targets could therefore increase response rates and duration. Furthermore, with appropriate target concentrations defined, excessive side effects in patients using the current fixed dosing strategy may be prevented. This review provides a practical guideline for TDM for the currently approved TKIs at 28 February 2013. The focus of this article is on the elaboration of exposure and response relationships of TKIs with proposed pharmacokinetic targets, mainly Ctrough, and further on the interpretation of the pharmacokinetic targets with recommendations for dose titrations.
Paclitaxel and docetaxel are active against a range of human cancers. Their antitumor activity is based on stabilization of the microtubule dynamics and thereby disruption of the cell cycle. The ...taxanes are administered as intravenous solutions in a short administration schedule. Distribution of both taxanes is rapid, with large volumes of distribution and significant binding to plasma proteins. The metabolism of paclitaxel is mediated primarily by the P450 cytochrome enzymes CYP2C8 and CYP3A, whereas docetaxel is only metabolized by CYP3A4. The most common toxicities after intravenous administration are neutropenia, hypersensitivity reactions, neurotoxicity, and alopecia. Several new administration forms are in development; albumin-bound paclitaxel (Abraxane) has recently been registered. Oral formulations of taxanes have been developed, and several are now undergoing phase I trials. New formulations might improve efficacy and safety and could be easier to use.
Abstract 5-Fluorouracil (5-FU) and capecitabine (CAP) are among the most frequently prescribed anticancer drugs. They are inactivated in the liver by the enzyme dihydropyrimidine dehydrogenase (DPD). ...Up to 5% of the population is DPD deficient and these patients have a significantly increased risk of severe and potentially lethal toxicity when treated with regular doses of 5-FU or CAP. DPD is encoded by the gene DPYD and variants in DPYD can lead to a decreased DPD activity. Although prospective DPYD genotyping is a valuable tool to identify patients with DPD deficiency, and thus those at risk for severe and potential life-threatening toxicity, prospective genotyping has not yet been implemented in daily clinical care. Our goal was to present the available evidence in favour of prospective genotyping, including discussion of unjustified worries on cost-effectiveness, and potential underdosing. We conclude that there is convincing evidence to implement prospective DPYD genotyping with an upfront dose adjustment in DPD deficient patients. Immediate benefit in patient care can be expected through decreasing toxicity, while maintaining efficacy.
Abstract Pharmacokinetic–pharmacodynamic modeling using non-linear mixed effects modeling (NONMEM) is a powerful yet challenging technique, as the software is generally accessed from the command ...line. A graphical user interface, Piraña, was developed that offers a complete modeling environment for NONMEM, enabling both novice and advanced users to increase efficiency of their workflow. Piraña provides features for the management and creation of model files, the overview of modeling results, creation of run reports and handling of datasets and output tables, and the running of custom R scripts on model output. Through the secure shell (SSH) protocol, Piraña can also be used to connect to Linux clusters (SGE, MOSIX) for distribution of workload. Modeling with NONMEM is computationally burdensome, which may be alleviated by distributing runs to computer clusters. A solution to this problem is offered here, called PCluster. This platform is easy to set up, runs in standard network environments, and can be extended with additional nodes if needed. The cluster supports the modeling toolkit Perl speaks NONMEM (PsN), and can include dedicated or non-dedicated PCs. A daemon script, written in Perl, was designed to run in the background on each node in the cluster, and to manage job distribution. The PCluster can be accessed from Piraña, and both software products have extensively been tested on a large academic network. The software is available under an open-source license.
To explore the effect of dihydropyrimidine dehydrogenase (DPD) single nucleotide polymorphisms (SNP) and haplotypes on outcome of capecitabine.
Germline DNA was available from 568 previously ...untreated patients with advanced colorectal cancer participating in the CAIRO2 trial, assigned to capecitabine, oxaliplatin, and bevacizumab ± cetuximab. The coding region of dihydropyrimidine dehydrogenase gene (DPYD) was sequenced in 45 cases with grade 3 or more capecitabine-related toxicity and in 100 randomly selected controls (cohort). Most discriminating (P < 0.1) or frequently occurring (>1%) nonsynonymous SNPs were analyzed in all 568 patients. SNPs and haplotypes were associated with toxicity, capecitabine dose modifications, and survival.
A total of 29 SNPs were detected in the case-cohort analysis, of which 8 were analyzed in all 568 patients. Of the patients polymorphic for DPYD IVS14+1G>A, 2846A>T, and 1236G>A, 71% (5 of 7), 63% (5 of 8), and 50% (14 of 28) developed grade 3 to 4 diarrhea, respectively, compared with 24% in the overall population. All patients polymorphic for IVS14+1G>A developed any grade 3 to 4 toxicity, including one possibly capecitabine-related death. Because of toxicity, a mean capecitabine dose reduction of 50% was applied in IVS14+1G>A and 25% in 2846A>T variant allele carriers. Patients were categorized into six haplotype groups: one predicted for reduced (10%), and two for increased risks (41% and 33%) for severe diarrhea. Individual SNPs were not associated with overall survival, whereas one haplotype was associated with overall survival HR (95% CI) = 0.57 (0.35-0.95).
DPYD IVS14+1G>A and 2846A>T predict for severe toxicity to capecitabine, for which patients require dose reductions. Haplotypes assist in selecting patients at risk for toxicity to capecitabine.
Patients with metastatic colorectal cancer with the
V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone ...has limited activity because of pathway reactivation through epidermal growth factor receptor signaling.
In this open-label, phase 3 trial, we enrolled 665 patients with
V600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators' choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis.
The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval CI, 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group.
A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the
V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.).
The purpose of this guideline is to provide information for the interpretation of clinical dihydropyrimidine dehydrogenase (DPYD) genotype tests so that the results can be used to guide dosing of ...fluoropyrimidines (5‐fluorouracil and capecitabine). Detailed guidelines for the use of fluoropyrimidines, their clinical pharmacology, as well as analyses of cost‐effectiveness are beyond the scope of this document. The Clinical Pharmacogenetics Implementation Consortium (CPIC®) guidelines consider the situation of patients for which genotype data are already available (updates available at https://cpicpgx.org/guidelines/guideline‐for‐fluoropyrimidines‐and‐dpyd/).
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