Highly variable absorption of clavulanic acid during the day: a population pharmacokinetic analysis.
Objectives: To calculate the clavulanic acid exposure of oral amoxicillin/clavulanic acid dosing regimens, to investigate variability using a population pharmacokinetic model and to explore target attainment using Monte Carlo simulations.Methods: Two groups of healthy male volunteers received amoxic...
| Published in: | Journal of Antimicrobial Chemotherapy (JAC) Vol. 73; no. 2; pp. 469 - 477 |
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| Main Authors: | , , , , |
| Format: | research Journal Article |
| Published: |
Oxford University Press / USA
Feb2018
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| Online Access: | View this record in EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=127550260&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 127550260 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 03057453 N5O jtl: Journal of Antimicrobial Chemotherapy (JAC) issn: 03057453 maglogo: N pubinfo: dt: Feb2018 vid: 73 iid: 2 pid: 622 pub: Oxford University Press / USA artinfo: ui: 127550260 127550260 NLM29136160 127550260 10.1093/jac/dkx376 NLM29136160 127550260 ppf: 469 ppct: 8 formats: tig: atl: Highly variable absorption of clavulanic acid during the day: a population pharmacokinetic analysis. aug: au: Mouton, Johan W. De Velde, Femke De Winter, Brenda C. M. Van Gelder, Teun Koch, Birgit C. P. affil: Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands sug: subj: Enzyme Inhibitors Pharmacokinetics Enzyme Inhibitors Administration and Dosage Systems Analysis Blood Chemical Analysis Research Subjects Adult Antibiotics Pharmacokinetics Human Young Adult Antibiotics Administration and Dosage Middle Age Crossover Design Adolescence Biological Availability Male Validation Studies Comparative Studies Evaluation Research Multicenter Studies Adult: 19-44 years Middle Aged: 45-64 years Adolescent: 13-18 years Male ab: Objectives: To calculate the clavulanic acid exposure of oral amoxicillin/clavulanic acid dosing regimens, to investigate variability using a population pharmacokinetic model and to explore target attainment using Monte Carlo simulations.Methods: Two groups of healthy male volunteers received amoxicillin/clavulanic acid tablets at the start of a standard meal on two separate days 1 week apart. One group (n = 14) received 875/125 mg q12h and 500/125 mg q8h and the other group (n = 15) received 500/125 mg q12h and 250/125 mg q8h. In total, 1479 blood samples were collected until 8-12 h after administration. Concentrations were analysed using non-compartmental (WinNonLin) and population pharmacokinetic (NONMEM) methods.Results: Median Cmax and AUC0-8 were 2.21 mg/L (0.21-4.35) and 4.99 mg·h/L (0.44-8.31), respectively. In 40/58 daily concentration-time profiles, Cmax and AUC0-8 of the morning dose were higher than with later doses. The final population model included a lag time (0.447 h), first-order absorption (3.99 h-1 at 8:00 h, between-subject variability 52.8%, between-occasion variability 48.5%), one distribution compartment (33.0 L, between-subject variability 23.9%) and first-order elimination (24.6 L/h, between-subject variability 26.7%). Bioavailability (fixed at 1 at 8:00 h, between-occasion variability 28.2%) and absorption rate decreased over the day. For 97.5% of the simulated population after 125 mg q12h or q8h, %fT > Ct at 0.5 mg/L was 8.33% (q12h) and 15.2% (q8h), %fT > Ct at 1 mg/L was 0% (q12h + q8h), and fAUC0-24 was 3.61 (q12h) and 5.56 (q8h) mg·h/L.Conclusions: Clavulanic acid absorption in healthy volunteers is highly variable. Bioavailability and absorption rate decrease over the day. The model developed here may serve to suggest clavulanic acid dosing regimens to optimize efficacy and prevent underdosing. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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