Dataset Information

Randomized study of individualized pharmacokinetically-guided dosing of paclitaxel compared with body-surface area dosing in Chinese patients with advanced non-small cell lung cancer.

ABSTRACT:

Aims

This prospective, randomized study was initiated to assess the impact of pharmacokinetically (PK)-guided paclitaxel (PTX) dosing on toxicity and efficacy compared with body-surface area (BSA)-based dosing in Chinese non-small cell lung cancer patients.

Methods

A total of 319 stage IIIB/IV non-small cell lung cancer patients receiving first-line chemotherapy were enrolled. Patients were randomized to receive 3-weekly carboplatin plus PTX at a starting dose of 175 mg/m² with subsequent PTX dosing based on either BSA or PK-guided dosing targeting time above a PTX plasma concentration of 0.05 μmol/L (PTX_Tc > 0.05 ) between 26 and 31 hours. The primary safety endpoint was grade 4 haematological toxicity. The secondary endpoints were neuropathy, objective response rate, progression-free survival and overall survival.

Results

In total, 275 (86%) patients completed ≥2 cycles of chemotherapy (140 in BSA arm and 135 in PK arm). In cycle 1, with the same PTX dose, average PTX_Tc > 0.05 was 37 hours (range = 18-57 hours). Over cycles 2-4, patients in the PK arm had significantly lower average PTX doses and exposure compared with the BSA arm (128 vs 161 mg/m² , P < .0001 and 29 vs 35 hours, P < .0001). PK-guided dosing significantly reduced the cumulative incidence of grade 4 haematological toxicity (15% vs 24%, P = .004), grade 4 neutropenia (15% vs 23%, P = .009) and grade ≥ 2 neuropathy (8% vs 21%, P = .005). Objective response rate (32% vs 26%, P = .28) and overall survival (21.0 vs 24.0 months, P = .815) were similar in PK and BSA arms. Progression-free survival was slightly improved in PK arm (4.67 vs 4.17 months, P = .026).

Conclusion

PK-guided PTX dosing significantly reduced grade 4 haematological toxicities and grade ≥ 2 neuropathy without an adverse impact on clinical outcomes.

SUBMITTER: Zhang J

PROVIDER: S-EPMC6783603 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Publications

Randomized study of individualized pharmacokinetically-guided dosing of paclitaxel compared with body-surface area dosing in Chinese patients with advanced non-small cell lung cancer.

Zhang Jie J Zhou Fei F Qi Huiwei H Ni Huijuan H Hu Qiong Q Zhou Caicun C Li Yunying Y Baburina Irina I Courtney Jodi J Salamone Salvatore J SJ

British journal of clinical pharmacology 20190614 10

<h4>Aims</h4>This prospective, randomized study was initiated to assess the impact of pharmacokinetically (PK)-guided paclitaxel (PTX) dosing on toxicity and efficacy compared with body-surface area (BSA)-based dosing in Chinese non-small cell lung cancer patients.<h4>Methods</h4>A total of 319 stage IIIB/IV non-small cell lung cancer patients receiving first-line chemotherapy were enrolled. Patients were randomized to receive 3-weekly carboplatin plus PTX at a starting dose of 175 mg/m<sup>2</s ...[more]

PMID: 31077432

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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.

Dataset Information

Randomized study of individualized pharmacokinetically-guided dosing of paclitaxel compared with body-surface area dosing in Chinese patients with advanced non-small cell lung cancer.

Aims

Methods

Results

Conclusion

Publications

Randomized study of individualized pharmacokinetically-guided dosing of paclitaxel compared with body-surface area dosing in Chinese patients with advanced non-small cell lung cancer.

Similar Datasets

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