Development and validation of a PBPK model of gepotidacin in rats to predict exposure in human prostate

Vincent Aranzana-Climent (1, 2) , Valentin Al Jalali (3) , Hwa-Ping Feng (4) , Karen O'Dwyer (4) , William Couet (1, 2, 5) , Markus Zeitlinger (3) , Sandrine Marchand (1, 2, 5)

1 Université de Poitiers - Faculté de Médecine et de Pharmacie
2 PHAR2 [Poitiers] - Pharmacologie des anti-infectieux et antibiorésistance [U 1070]
3 Medizinische Universität Wien = Medical University of Vienna
4 GSK - GlaxoSmithKline
5 CHU de Poitiers [La Milétrie] - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital

Background Gepotidacin is a novel antibiotic currently under development for uncomplicated urinary tract infection and uncomplicated gonorrhea in phase 3 by GSK. The objective of the current study was to assess the possibility of predicting human prostate pharmacokinetics by combining animal data and physiologically based pharmacokinetic (PBPK) modeling. Methods Twenty anesthetized rats were inserted with microdialysis probes in blood, muscle and prostate (approval n°202011711481557) gepotidacin (20 mg/kg, single dose) was administered by IV bolus. Extensive rat microdialysis samples were collected at up to 5h postdose. Human plasma and ex vivo prostate microdialysis samples after a single oral 1500 mg gepotidacin dose were collected as described in abstract 03279. Plasma and microdialysate concentrations were determined by LC-MS/MS. A PBPK model based on rat microdialysis data was developed exploring multiple structural approaches, it was translated to a human PBPK model by incorporating human physiological parameters from scaling, prediction or literature; human plasma PK parameters were estimated by fitting to observed data. The rat PBPK model was translated to a human PBPK model by incorporating human physiological parameters from scaling, prediction or literature values; human plasma PK parameters were estimated by fitting to observed data. Simulations using the rat and human PBPK models were performed to compare unbound tissue concentrations with observed. Results The best PBPK model structure was a flow limited reduced PBPK model. It described rat unbound plasma, muscle interstitium and prostate interstitium adequately as shown on figure 1 with more than 80% of the predicted concentrations within 2-fold of the observed concentrations. For human data, there was a general agreement between the mean predicted prostate concentrations and the observed mean unbound prostate concentrations as shown on figure 2 with 66.7% of the of the predicted concentrations within 2-fold of the observed concentrations. Conclusions A PBPK model was developed with rat microdialysis data, translated to a human PBPK model and adequately predicted human ex vivo prostate microdialysate data. Tissue penetration is one important aspect of an effective treatment for prostatitis but does not in itself indicate clinical efficacy.

Domaines: Pharmacologie

Vincent Aranzana-Climent, Valentin Al Jalali, Hwa-Ping Feng, Karen O'Dwyer, William Couet, et al.. Development and validation of a PBPK model of gepotidacin in rats to predict exposure in human prostate. 34th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), Apr 2024, Barcelona, Spain. ⟨hal-04571063⟩