Translating CYP2D6 genotype to metabolizer phenotype is not standardized across clinical laboratories offering pharmacogenetic (PGx) testing and PGx clinical practice guidelines, such as the Clinical ...Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG). The genotype to phenotype translation discordance between laboratories and guidelines can cause discordant cytochrome P450 2D6 (CYP2D6) phenotype assignments and, thus lead to inconsistent therapeutic recommendations and confusion among patients and clinicians. A modified‐Delphi method was used to obtain consensus for a uniform system for translating CYP2D6 genotype to phenotype among a panel of international CYP2D6 experts. Experts with diverse involvement in CYP2D6 interpretation (clinicians, researchers, genetic testing laboratorians, and PGx implementers; n = 37) participated in conference calls and surveys. After completion of 7 surveys, a consensus (> 70%) was reached with 82% of the CYP2D6 experts agreeing to the final CYP2D6 genotype to phenotype translation method. Broad adoption of the proposed CYP2D6 genotype to phenotype translation method by guideline developers, such as CPIC and DPWG, and clinical laboratories as well as researchers will result in more consistent interpretation of CYP2D6 genotype.
Despite advances in the field of pharmacogenetics (PGx), clinical acceptance has remained limited. The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing ...evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the starting dose optimization of three anti-cancer drugs (fluoropyrimidines: 5-fluorouracil, capecitabine and tegafur) to decrease the risk of severe, potentially fatal, toxicity (such as diarrhoea, hand-foot syndrome, mucositis or myelosuppression). Dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene) enzyme deficiency increases risk of fluoropyrimidine-induced toxicity. The DPYD-gene activity score, determined by four DPYD variants, predicts DPD activity and can be used to optimize an individual's starting dose. The gene activity score ranges from 0 (no DPD activity) to 2 (normal DPD activity). In case it is not possible to calculate the gene activity score based on DPYD genotype, we recommend to determine the DPD activity and adjust the initial dose based on available data. For patients initiating 5-fluorouracil or capecitabine: subjects with a gene activity score of 0 are recommended to avoid systemic and cutaneous 5-fluorouracil or capecitabine; subjects with a gene activity score of 1 or 1.5 are recommended to initiate therapy with 50% the standard dose of 5-fluorouracil or capecitabine. For subjects initiating tegafur: subjects with a gene activity score of 0, 1 or 1.5 are recommended to avoid tegafur. Subjects with a gene activity score of 2 (reference) should receive a standard dose. Based on the DPWG clinical implication score, DPYD genotyping is considered "essential", therefore directing DPYD testing prior to initiating fluoropyrimidines.
Pre‐emptive pharmacogenetics (PGx) testing of a panel of germline genetic variants represents a new model for personalized medicine. Clinical impact of PGx testing is maximized when all variant ...alleles for which actionable clinical guidelines are available are included in the test panel. However, no such standardized panel has been presented to date, impeding adoption, exchange, and continuity of PGx testing. We, therefore, developed such a panel, hereafter called the PGx‐Passport, based on the actionable Dutch Pharmacogenetics Working Group (DPWG) guidelines. Germline‐variant alleles were systematically selected using predefined criteria regarding allele population frequencies, effect on protein functionality, and association with drug response. A PGx‐Passport of 58 germline variant alleles, located within 14 genes (CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A5, DPYD, F5, HLA‐A, HLA‐B, NUDT15, SLCO1B1, TPMT, UGT1A1, and VKORC1) was composed. This PGx‐Passport can be used in combination with the DPWG guidelines to optimize drug prescribing for 49 commonly prescribed drugs.
Liposomes as pharmaceutical drug carriers were developed to increase antitumour efficacy and decrease drug toxicity. Doxorubicin HCl liposomal injection was the first liposomal encapsulated ...anticancer drug to receive clinical approval. To date, virtually all traditional anticancer drugs have been encapsulated in liposomes.
The majority of clinical studies only support the concept of a decreased toxicity and better tolerability of the liposomal anticancer drug. Although liposomal anticancer drugs have grown to maturity in several indications and are now in widespread further development programmes using their theoretical advantages to fulfil the high expectations, further studies are warranted – including the development of novel liposomal formulations.
Tamoxifen is biotransformed by CYP2D6 to 4‐hydroxytamoxifen and 4‐hydroxy N‐desmethyl tamoxifen (endoxifen), both with greater antiestrogenic potency than the parent drug. Patients with certain ...CYP2D6 genetic polymorphisms and patients who receive strong CYP2D6 inhibitors exhibit lower endoxifen concentrations and a higher risk of disease recurrence in some studies of tamoxifen adjuvant therapy of early breast cancer. We summarize evidence from the literature and provide therapeutic recommendations for tamoxifen based on CYP2D6 genotype.
The histone deacetylase inhibitors (HDACi) are a group of small molecules that target histone deacetylases (HDACs) by inhibiting their activity. HDACi have a long history of use in neurology and ...psychiatry as antiepileptics and mood stabilizers. More recently, they have been investigated as possible treatments for cancer. HDACi have undergone rapid clinical development in recent years, on the basis of their preclinical in-vitro and in-vivo antitumor activity in hematological malignancies and solid tumors. Many HDACi have entered phase I-III clinical trials. Among the HDACi, vorinostat and romidepsin are currently the most extensively studied. In 2006 and 2009, respectively, they received approval by the United States Food and Drug Administration for treatment of cutaneous T-cell lymphoma and romidepsin for the treatment of peripheral T-cell lymphoma. Other HDACi, such as panobinostat and valproic acid, also demonstrated activity as therapeutic anticancer agents. In this article we give an overview of the clinical studies of HDACi in solid tumors. We start with a short description of the working mechanism of HDACi in general.
For the treatment of Covid‐19 patients with remdesivir, poor renal and liver function were both exclusion criteria in randomized clinical trials and contraindication for treatment. Also, ...nephrotoxicity and hepatotoxicity are reported as adverse events. We retrospectively reviewed renal and liver functions of Covid‐19 103 patients who received remdesivir in the 15 days after treatment initiation. Approximately 20% of the patient population met randomized clinical trial exclusion criteria. In total, 11% of the patients had a decrease in estimated glomerular filtration rate >10 mL/min/1.73m2. Also, 25 and 35% had increased alanine transaminase and aspartate transaminase levels, respectively. However, serious adverse events were limited. Therefore, based on these preliminary results, contraindications based on kidney and liver function should not be absolute for remdesivir treatment in patients with Covid‐19 if these functions are monitored regularly. A larger patient cohort is warranted to confirm our results.
Aims
Tacrolimus and mycophenolic acid dosing after renal transplantation is individualized through therapeutic drug monitoring (TDM). Home‐based dried blood spot (DBS) sampling has the potential to ...replace conventional TDM sampling at the clinic. A liquid chromatography–tandem mass spectrometry (LC–MS/MS) assay was developed to quantify tacrolimus and mycophenolic acid in DBS and clinically validated for abbreviated area under the concentration–time curve (AUC) monitoring using an innovative volumetric DBS sampling device.
Methods
Clinical validation was performed by direct comparison of paired DBS and whole blood (WB) (tacrolimus) and plasma (mycophenolic acid) concentrations and AUCs. Agreement was evaluated using Passing–Bablok regression, Bland–Altman analysis and DBS‐to‐WB predictive performance. TDM dosing recommendations based on both methods were compared to assess clinical impact.
Results
Paired tacrolimus (n = 200) and mycophenolic acid (n = 192) DBS and WB samples were collected from 65 kidney(–pancreas) transplant recipients. Differences for tacrolimus and mycophenolic acid were within ±20% for 84.5% and 76.6% of concentrations and 90.5% and 90.7% of AUCs, respectively. Tacrolimus and mycophenolic acid dosing recommendation differences occurred on 44.4% and 4.7% of occasions. Tacrolimus DBS dosing recommendations were 0.35 ± 0.14 mg higher than for WB and 8 ± 3% of the initial dose. Mycophenolic acid DBS dosing recommendations were 23.3 ± 31.9 mg lower than for plasma and 2 ± 3.5% of the initial dose.
Conclusions
Tacrolimus and mycophenolic acid TDM for outpatient renal transplant recipients, based on abbreviated AUC collected with a DBS sampling device, is comparable to conventional TDM based on WB sampling. Patient training and guidance on good blood‐spotting practices is essential to ensure method feasibility.
Increasing knowledge of intertumor heterogeneity, intratumor heterogeneity, and cancer evolution has improved the understanding of anticancer treatment resistance. A better characterization of cancer ...evolution and subsequent use of this knowledge for personalized treatment would increase the chance to overcome cancer treatment resistance. Model‐based approaches may help achieve this goal. In this review, we comprehensively summarized mathematical models of tumor dynamics for solid tumors and of drug resistance evolution. Models displayed by ordinary differential equations, algebraic equations, and partial differential equations for characterizing tumor burden dynamics are introduced and discussed. As for tumor resistance evolution, stochastic and deterministic models are introduced and discussed. The results may facilitate a novel model‐based analysis on anticancer treatment response and the occurrence of resistance, which incorporates both tumor dynamics and resistance evolution. The opportunities of a model‐based approach as discussed in this review can be of great benefit for future optimizing and personalizing anticancer treatment.
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