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Pharmacokinetically guided algorithm of 5-fluorouracil dosing, a reliable strategy of precision chemotherapy for solid tumors: a meta-analysis.

ABSTRACT: Precision medicine characterizes a new era of cancer care and provides each patient with the right drug at the right dose and time. However, the practice of precision dosing is hampered by a lack of smart dosing algorithms. A pharmacokinetically guided (PKG) dosing algorithm is considered to be the leading strategy for precision chemotherapy, although the effects of PKG dosing are not completely confirmed. Hence, we conducted a meta-analysis to evaluate the effects of the PKG algorithm of 5-fluorouracil (5-FU) dosing on patients with solid tumors. A comprehensive retrieval was performed to identify all of the prospective controlled studies that compared the body surface area (BSA)-based algorithm with the PKG algorithm of 5-FU in patients with solid tumors. Overall, four studies with 504 patients were included. The PKG algorithm significantly improved the objective response rate of 5-FU-based chemotherapy compared with the BSA-based algorithm. Furthermore, PKG dosing markedly decreased the risk of total grade 3/4 adverse drug reactions, especially those related to hematological toxicity. Overall, the PKG algorithm may serve as a reliable strategy for individualized dosing of 5-FU.

SUBMITTER: Fang L

PROVIDER: S-EPMC4882511 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Pharmacokinetically guided algorithm of 5-fluorouracil dosing, a reliable strategy of precision chemotherapy for solid tumors: a meta-analysis.

Fang Luo L Xin Wenxiu W Ding Haiying H Zhang Yiwen Y Zhong Like L Luo Hong H Li Jingjing J Yang Yunshan Y Huang Ping P

Scientific reports 20160527

Precision medicine characterizes a new era of cancer care and provides each patient with the right drug at the right dose and time. However, the practice of precision dosing is hampered by a lack of smart dosing algorithms. A pharmacokinetically guided (PKG) dosing algorithm is considered to be the leading strategy for precision chemotherapy, although the effects of PKG dosing are not completely confirmed. Hence, we conducted a meta-analysis to evaluate the effects of the PKG algorithm of 5-fluo ...[more]

PMID: 27229175

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Project description:ImportanceChildren of all ages appear susceptible to severe acute respiratory syndrome coronavirus 2 infection. To support pediatric clinical studies for investigational treatments of coronavirus disease 2019 (COVID-19), pediatric-specific dosing is required.ObjectiveTo define pediatric-specific dosing regimens for hydroxychloroquine and remdesivir for COVID-19 treatment.Design, setting, and participantsPharmacokinetic modeling and simulation were used to extrapolate investigated adult dosages toward children (March 2020-April 2020). Physiologically based pharmacokinetic modeling was used to inform pediatric dosing for hydroxychloroquine. For remdesivir, pediatric dosages were derived using allometric-scaling with age-dependent exponents. Dosing simulations were conducted using simulated pediatric and adult participants based on the demographics of a white US population.InterventionsSimulated drug exposures following a 5-day course of hydroxychloroquine (400 mg every 12 hours × 2 doses followed by 200 mg every 12 hours × 8 doses) and a single 200-mg intravenous dose of remdesivir were computed for simulated adult participants. A simulation-based dose-ranging study was conducted in simulated children exploring different absolute and weight-normalized dosing strategies.Main outcomes and measuresThe primary outcome for hydroxychloroquine was average unbound plasma concentrations for 5 treatment days. Additionally, unbound interstitial lung concentrations were simulated. For remdesivir, the primary outcome was plasma exposure (area under the curve, 0 to infinity) following single-dose administration.ResultsFor hydroxychloroquine, the physiologically based pharmacokinetic model analysis included 500 and 600 simulated white adult and pediatric participants, respectively, and supported weight-normalized dosing for children weighing less than 50 kg. Geometric mean-simulated average unbound plasma concentration values among children within different developmental age groups (32-35 ng/mL) were congruent to adults (32 ng/mL). Simulated unbound hydroxychloroquine concentrations in lung interstitial fluid mirrored those in unbound plasma and were notably lower than in vitro concentrations needed to mediate antiviral activity. For remdesivir, the analysis included 1000 and 6000 simulated adult and pediatric participants, respectively. The proposed pediatric dosing strategy supported weight-normalized dosing for participants weighing less than 60 kg. Geometric mean-simulated plasma area under the time curve 0 to infinity values among children within different developmental age-groups (4315-5027 ng × h/mL) were similar to adults (4398 ng × h/mL).Conclusions and relevanceThis analysis provides pediatric-specific dosing suggestions for hydroxychloroquine and remdesivir and raises concerns regarding hydroxychloroquine use for COVID-19 treatment because concentrations were less than those needed to mediate an antiviral effect.

Project description:Warfarin is the most common oral anticoagulant. Because of a narrow therapeutic range, interindividual differences in drug responses, and the risk of bleeding, there are many challenges in using warfarin. We need to predict the warfarin maintenance dose. However, ethnic-specific algorithms may be required, and some Chinese algorithms do not perform adequately. Therefore, we aimed to establish a Han Chinese appropriate algorithm.We recruited a study group consisting of 361 Han Chinese patients receiving warfarin treatment who had heart valve replacements. Genotyping of 38 single nucleotide polymorphisms (SNPs) in 13 candidate genes was carried out using the MassARRAY. In the derivation cohort, a multiple linear regression model was constructed to predict the warfarin dosage. We evaluated the accuracy of our algorithm in the validation cohort and compared it with the other 5 algorithms based on Han Chinese and other races.We established a Han Chinese-specific pharmacogenetic-guided warfarin dosing algorithm. Warfarin maintenance dosage (mg/day) = 1.787 - 0.023 × (Age) + 1.151 × (BSA [m]) + 0.917 × (VKORC1 AG) + 4.619 × (VKORC1 GG) + 0.595 × (CYP4F2 TT) + 0.707 × (CYP2C19 CC). It explained 58.3% of the variance in warfarin doses in Han Chinese patients and was superior to the other 5 algorithms. The ability of the 6 algorithms which estimate the required dose correctly was tested. Our model had a mean absolute error of 0.74 mg/day, the other 5 models have mean absolute error of 0.81 mg/day,1.05 mg/day, 1.24 mg/day, 1.18 mg/day, and 0.85 mg/day, respectively. Our model had a mean percentage error of 26.9%, the other 5 models have the mean percentage error of 27.7%, 27.2%, 52.3%, 45.7%, and 29.3%, respectively.Physicians can not adopt algorithm from other race directly to predict warfarin dose in patients with heart valve replacements, they should establish a new algorithm or adjust another algorithm to fit their patients. The algorithm established in this study has the potential to assist physicians in determining warfarin doses that are close to the appropriate doses.

Dataset Information

Pharmacokinetically guided algorithm of 5-fluorouracil dosing, a reliable strategy of precision chemotherapy for solid tumors: a meta-analysis.

Publications

Pharmacokinetically guided algorithm of 5-fluorouracil dosing, a reliable strategy of precision chemotherapy for solid tumors: a meta-analysis.

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