C. Ambery(1), M. Beerahee(1)
(1) Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, United Kingdom
Introduction: A novel IV anti-inflammatory drug is in development for the treatment of infectious disease. Clinical proof-of-pharmacology was demonstrated in healthy subjects by biomarker inhibition as well as for predecessor compound where 50-70% inhibition of biomarker was associated with 75% inhibition of inflammatory marker. A biomarker PK/PD relationship has previously been described by two-step sequential modelling. This is a Phase 2 dose selection case study for a new Captisol (sulfobutylether-beta-cyclodextrin, a solubilising agent) IV formulation. Captisol is well tolerated in healthy subjects, however clearance is delayed in renal impairment [3], a clinical concern given disease. Drug exposure limitation based on toxicology findings was also imposed for the novel drug.
Objectives: Phase 2 dose selection based on 1) Captisol exposure limitations, 2) drug exposure limitations, and 3) biomarker-response relationship.
Methods: Captisol: Captisol literature review performed [1,5]. Captisol PK model of [4] used to create Berkeley Madonna (BM) simulation model. BM model used to simulate new drug scenarios. To enable simulation across spectrum of renal function the relationship between Captisol plasma clearance and creatinine clearance was defined by use of digitised data from Fig.4(B) of [3] and Fig.2 of [4] excluding renal dysfunction subjects during hemodialysis data. A linear model was fitted to the digitised data. Safety: Simulations to predict the proportion of subjects exceeding the exposure limit based on toxicological findings were performed. One thousand NONMEM trial simulations of 100 subjects per dose level were performed for each dose scenario. Biomarker: The predicted exposures from the safety simulation were used to perform sequential biomarker simulations. One thousand NONMEM trial simulations of 100 subjects per dose level were performed for each dose scenario. The level of biomarker inhibition at Ctrough and Cavg was evaluated.
Results: Captisol simulated over creatinine clearance range 10 to 120 mL/min [2]. For formulation ratio of Captisol to novel drug, levels within previous clinical experience, mitigating clinical concern. Top dose selected based on minimising proportion of subjects exceeding safety limit. Figure 1 shows predicted biomarker inhibition for Cavg dose scenarios.
Conclusions: Simulation of biomarker exposure-response relationship, together with Captisol and drug concentration facilitated selection of Phase 2 dose.
References:
[1] Abel S, Allan R, Gandelman K, Tomaszewski K, Webb DJ, Wood ND. Pharamcokinetics, safety and tolerance of voriconazole in renally impaired subjects. Clin Drug Res. 2008;28(7):409-420.
[2] Guidance for Industry: pharmacokinetics in patients with impaired renal function – study design, data analysis, and impact on dosing and labelling. Rockville (MD): US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and research, 1998 May.
[3] Luke DR, Tomaszewski K, Damle B, Schlamn HT. Review of basic and clinical pharmacology of sulfobutylether-β-cyclodextrin (SBECD). J Pharma Sci. 2010;99(8):3291-3301.
[4] Luke DR, Wood ND, Tomaszewski K, Damle B. Pharmacokinetics of sulfobutylether-β-cyclodextrin (SBECD) in subjects on hemodialysis. Nephrol Dial Transplant. 2012;27:1207-1212.
[5] Turner RB, Martello JL, Malhotra A. Worsening renal function in patients with baseline renal impairment treated with intravenous voriconazole: A systematic review. Int J Antimicrob Agents. 2015;46(4):362-366.
Reference: PAGE 25 (2016) Abstr 5921 [www.page-meeting.org/?abstract=5921]
Poster: Methodology - Study Design