Lisanne A. H. Bevers, Anne E. M. Kamphuis, L. C. Wendy van der Wekken-Pas, Rory Leisegang, David M. Burger, Angela Colbers
{"title":"健康志愿者服用多罗替拉韦(DTG)和恩曲他滨/富马酸替诺福韦/富马酸阿拉非那胺(F/TAF)儿科片剂的相对生物利用度","authors":"Lisanne A. H. Bevers, Anne E. M. Kamphuis, L. C. Wendy van der Wekken-Pas, Rory Leisegang, David M. Burger, Angela Colbers","doi":"10.1007/s40262-024-01365-4","DOIUrl":null,"url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background and objective</h3><p>Within the UNIVERSAL project (RIA2019PD-2882) we aim to develop a paediatric dolutegravir (DTG)/emtricitabine (FTC or F)/tenofovir alafenamide (TAF) fixed-dose combination. To inform dosing of this study, we undertook a relative bioavailability (RBA) study in healthy volunteers to investigate a potential pharmacokinetic effect when paediatric formulations of DTG and F/TAF are taken together.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Participants received all of the following treatments as paediatric formulations in randomised order: a single dose of 180/22.5 mg F/TAF; a single dose of 30 mg DTG; a single dose of 180/22.5 mg F/TAF plus 30 mg DTG. Blood concentrations of DTG, FTC, TAF, and tenofovir (TFV) were measured over 48 h post-dose. If the 90% confidence intervals (CIs) of the geometric least squares mean (GLSM) ratios of area under the curve (AUC) and maximum concentration (<i>C</i><sub>max</sub>) of each compound were within 0.70–1.43, we considered this as no clinically relevant PK interaction.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>A total of 15 healthy volunteers were included. We did not observe a clinically relevant PK interaction between the paediatric DTG and F/TAF formulations for the compounds DTG, FTC, and TFV. For TAF, the lower boundaries of the 90% CIs of the GLSM ratios of the AUC<sub>0–∞</sub> and <i>C</i><sub>max</sub> fell outside our acceptance criteria of 0.70–1.43.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>Although TAF AUC and <i>C</i><sub>max</sub> 90% CIs fell outside the pre-defined criteria (0.62–1.11 and 0.65–1.01, respectively), no consistent effect on TAF PK was observed, likely due to high inter-subject variability. Moreover, there are several reasons to rely on TFV exposure as being more clinically relevant than TAF exposure. Therefore, we found no clinically relevant interactions in this study.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":4.6000,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Relative Bioavailability of Dolutegravir (DTG) and Emtricitabine/Tenofovir Alafenamide Fumarate (F/TAF) Administered as Paediatric Tablet Formulations in Healthy Volunteers\",\"authors\":\"Lisanne A. H. Bevers, Anne E. M. Kamphuis, L. C. Wendy van der Wekken-Pas, Rory Leisegang, David M. Burger, Angela Colbers\",\"doi\":\"10.1007/s40262-024-01365-4\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<h3 data-test=\\\"abstract-sub-heading\\\">Background and objective</h3><p>Within the UNIVERSAL project (RIA2019PD-2882) we aim to develop a paediatric dolutegravir (DTG)/emtricitabine (FTC or F)/tenofovir alafenamide (TAF) fixed-dose combination. To inform dosing of this study, we undertook a relative bioavailability (RBA) study in healthy volunteers to investigate a potential pharmacokinetic effect when paediatric formulations of DTG and F/TAF are taken together.</p><h3 data-test=\\\"abstract-sub-heading\\\">Methods</h3><p>Participants received all of the following treatments as paediatric formulations in randomised order: a single dose of 180/22.5 mg F/TAF; a single dose of 30 mg DTG; a single dose of 180/22.5 mg F/TAF plus 30 mg DTG. Blood concentrations of DTG, FTC, TAF, and tenofovir (TFV) were measured over 48 h post-dose. If the 90% confidence intervals (CIs) of the geometric least squares mean (GLSM) ratios of area under the curve (AUC) and maximum concentration (<i>C</i><sub>max</sub>) of each compound were within 0.70–1.43, we considered this as no clinically relevant PK interaction.</p><h3 data-test=\\\"abstract-sub-heading\\\">Results</h3><p>A total of 15 healthy volunteers were included. We did not observe a clinically relevant PK interaction between the paediatric DTG and F/TAF formulations for the compounds DTG, FTC, and TFV. For TAF, the lower boundaries of the 90% CIs of the GLSM ratios of the AUC<sub>0–∞</sub> and <i>C</i><sub>max</sub> fell outside our acceptance criteria of 0.70–1.43.</p><h3 data-test=\\\"abstract-sub-heading\\\">Conclusions</h3><p>Although TAF AUC and <i>C</i><sub>max</sub> 90% CIs fell outside the pre-defined criteria (0.62–1.11 and 0.65–1.01, respectively), no consistent effect on TAF PK was observed, likely due to high inter-subject variability. Moreover, there are several reasons to rely on TFV exposure as being more clinically relevant than TAF exposure. 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Relative Bioavailability of Dolutegravir (DTG) and Emtricitabine/Tenofovir Alafenamide Fumarate (F/TAF) Administered as Paediatric Tablet Formulations in Healthy Volunteers
Background and objective
Within the UNIVERSAL project (RIA2019PD-2882) we aim to develop a paediatric dolutegravir (DTG)/emtricitabine (FTC or F)/tenofovir alafenamide (TAF) fixed-dose combination. To inform dosing of this study, we undertook a relative bioavailability (RBA) study in healthy volunteers to investigate a potential pharmacokinetic effect when paediatric formulations of DTG and F/TAF are taken together.
Methods
Participants received all of the following treatments as paediatric formulations in randomised order: a single dose of 180/22.5 mg F/TAF; a single dose of 30 mg DTG; a single dose of 180/22.5 mg F/TAF plus 30 mg DTG. Blood concentrations of DTG, FTC, TAF, and tenofovir (TFV) were measured over 48 h post-dose. If the 90% confidence intervals (CIs) of the geometric least squares mean (GLSM) ratios of area under the curve (AUC) and maximum concentration (Cmax) of each compound were within 0.70–1.43, we considered this as no clinically relevant PK interaction.
Results
A total of 15 healthy volunteers were included. We did not observe a clinically relevant PK interaction between the paediatric DTG and F/TAF formulations for the compounds DTG, FTC, and TFV. For TAF, the lower boundaries of the 90% CIs of the GLSM ratios of the AUC0–∞ and Cmax fell outside our acceptance criteria of 0.70–1.43.
Conclusions
Although TAF AUC and Cmax 90% CIs fell outside the pre-defined criteria (0.62–1.11 and 0.65–1.01, respectively), no consistent effect on TAF PK was observed, likely due to high inter-subject variability. Moreover, there are several reasons to rely on TFV exposure as being more clinically relevant than TAF exposure. Therefore, we found no clinically relevant interactions in this study.
期刊介绍:
Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics.
Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.