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Pharmacokinetically guided sunitinib dosing: a feasibility study in patients with advanced solid tumours.

ABSTRACT: Plasma exposure of sunitinib shows large inter-individual variation. Therefore, a pharmacokinetic (PK) study was performed to determine safety and feasibility of sunitinib dosing based on PK levels.Patients were treated with sunitinib 37.5?mg once daily. At days 15 and 29 of treatment, plasma trough levels of sunitinib and N-desethyl sunitinib were measured. If the total trough level (TTL) was <50?ng?ml(-1) and the patient did not show any grade ?3 toxicity, the daily sunitinib dose was increased by 12.5?mg. If the patient suffered from grade ?3 toxicity, the sunitinib dose was lowered by 12.5?mg.Twenty-nine out of 43 patients were evaluable for PK assessments. Grade ?3 adverse events were experienced in seven patients (24%) at the starting dose and in nine patients (31%) after dose escalation. TTLs were below target in 15 patients (52%) at the starting dose. Of these, five patients (17%) reached target TTL after dose escalation without additional toxicity.In a third of the patients that were below target TTL at standard dose, the sunitinib dose could be increased without additional toxicities. This could be the basis for future studies and the implementation of a PK-guided dosing strategy in clinical practice.

SUBMITTER: Lankheet NA

PROVIDER: S-EPMC4021528 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Pharmacokinetically guided sunitinib dosing: a feasibility study in patients with advanced solid tumours.

Lankheet N A G NA Kloth J S L JS Gadellaa-van Hooijdonk C G M CG Cirkel G A GA Mathijssen R H J RH Lolkema M P J K MP Schellens J H M JH Voest E E EE Sleijfer S S de Jonge M J A MJ Haanen J B A G JB Beijnen J H JH Huitema A D R AD Steeghs N N

British journal of cancer 20140415 10

<h4>Background</h4>Plasma exposure of sunitinib shows large inter-individual variation. Therefore, a pharmacokinetic (PK) study was performed to determine safety and feasibility of sunitinib dosing based on PK levels.<h4>Methods</h4>Patients were treated with sunitinib 37.5 mg once daily. At days 15 and 29 of treatment, plasma trough levels of sunitinib and N-desethyl sunitinib were measured. If the total trough level (TTL) was <50 ng ml(-1) and the patient did not show any grade ⩾3 toxicity, th ...[more]

PMID: 24736581

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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

Pharmacokinetically guided sunitinib dosing: a feasibility study in patients with advanced solid tumours.

Publications

Pharmacokinetically guided sunitinib dosing: a feasibility study in patients with advanced solid tumours.

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