title: Population Pharmacokinetic Model of Doxycycline Plasma Concentrations Using Pooled Study Data.
abstract: The literature presently lacks a population pharmacokinetic analysis of doxycycline. This study aimed to develop a population pharmacokinetic model of doxycycline plasma concentrations that could be used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC. Doxycycline pharmacokinetic data were available from eight phase 1 clinical trials following single/multiple doses of conventional-release doxycycline capsules, Doryx delayed-release tablets, and Doryx MPC under fed and fasted conditions. A population pharmacokinetic model was developed in a stepwise manner using NONMEM, version 7.3. The final covariate model was developed according to a forward inclusion (P< 0.01) and then backward deletion (P< 0.001) procedure. The final model was a two-compartment model with two-transit absorption compartments. Structural covariates in the base model included formulation effects on relative bioavailability (F), absorption lag (ALAG), and the transit absorption rate (KTR) under the fed status. An absorption delay (lag) for the fed status (FTLAG2 = 0.203 h) was also included in the model as a structural covariate. The fed status was observed to decreaseFby 10.5%, and the effect of female sex was a 14.4% increase in clearance. The manuscript presents the first population pharmacokinetic model of doxycycline plasma concentrations following oral doxycycline administration. The model was used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC, and it could potentially be used to critically examine and optimize doxycycline dose regimens.
authors.affiliation: Australian Centre for Pharmacometrics and Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia ashley.hopkins@mymail.unisa.edu.au.
authors.forename: Ashley M
authors.identifier: 0000-0001-7652-4378
authors.initials: AM
authors.lastname: Hopkins
authors.affiliation: Australian Centre for Pharmacometrics and Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Wojciechowski
authors.affiliation: Australian Centre for Pharmacometrics and Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Ahmad Y
authors.identifier: 0000-0002-4182-065X
authors.initials: AY
authors.lastname: Abuhelwa
authors.affiliation: Mayne Pharma International, Salisbury South, South Australia, Australia.
authors.forename: Stuart
authors.initials: S
authors.lastname: Mudge
authors.affiliation: Australian Centre for Pharmacometrics and Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Upton
authors.affiliation: Australian Centre for Pharmacometrics and Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: David J R
authors.initials: DJ
authors.lastname: Foster
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D017321:Clinical Trials, Phase I as Topic; D004318:Doxycycline / Q000097:blood / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D012737:Sex Factors; D013607:Tablets; D013810:Therapeutic Equivalency
chemical_list: D000900:Anti-Bacterial Agents; D013607:Tablets; D004318:Doxycycline
keywords: doxycycline; population pharmacokinetics