In Silico Pharmacokinetic/Pharmacodynamic Simulation Of Long Acting Tenofovir Injectable Formulation For Pre-exposure Prophylaxis Strategies
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1 In Silico Pharmacokinetic/Pharmacodynamic Simulation Of Long Acting Tenofovir Injectable Formulation For Pre-exposure Prophylaxis Strategies Paul Curley, Darren Moss, Rajith K R Rajoli, James Hobson, Caren L. Freel Meyers, Charles Flexner, Steve Rannard, Andrew Owen and Marco Siccardi
2 Introduction PrEP offers a promising strategy to reduction of HIV acquisition 18 studies investigating PrEP in various high risk populations >7% efficacy (vs placebo) with no increase in adverse events* iprex study demonstrated 44% efficacy** When accounting for detectable drug, >9% efficacy *Fonner et al 216, **Anderson et al 212,
3 Introduction??????? In silico simulation Release Rate Dose Frequency
4 Introduction
5 Introduction Predicted relationship between intracellular TFV-DP and extent of protection from HIV acquisition HIV incidence/1 P-Y (iprex) BLQ % - 3 fmol/1 6 cells (95% CI, <1-7) 9% - 16 fmol/1 6 cells (95% CI, 3-28) 99% - 33 fmol/1 6 cells (95% CI, 6-6) Placebo TDF-FTC TFV-DP (fmol/16 PBMCs) Anderson et al 212
6 Introduction Predicted relationship between intracellular TFV-DP and extent of protection from HIV acquisition HIV incidence/1 P-Y (iprex) Placebo 5% - 3 fmol/1 6 cells (95% CI, <1-7) 9% - 16 fmol/1 6 cells (95% CI, 3-28) 99% - 33 fmol/1 6 cells (95% CI, 6-6) TDF-FTC BLQ TFV-DP (fmol/16 PBMCs) Aims To assess the feasibility of long acting injectables of TFV Identify dose and release rates for PrEP Anderson et al 212
7 Methods Adipose Bones Brain Muscle Skin Gonads Thymus Lungs Veins Pancreas RV Heart Tissue IM Depot Capillaries LV Arteries Spleen Stomach Tissue Stomach Portal Vein Small Intestine Tissue Liver Intestinal Metabolism Kidneys Metabolism Elimination
8 Methods V max Adipose Bones Brain TFV plasma K m Muscle Skin Gonads Thymus Veins Pancreas Lungs RV Heart Tissue LV IM Depot Capillaries Arteries K in TFV-DP Spleen Stomach Tissue Stomach Portal Vein Small Intestine Tissue Liver Intestinal Metabolism Kidneys Metabolism Elimination K out Duwal et al 212
9 Methods Solubility Age Brain Absorption Apparent Permeability BMI Adipose Cardiac Output Distribution Drug Partition Coefficient Height Liver Kidneys Metabolism Protein Binding Weight Skin Other Tissues Elimination Lipophilicity Blood-to-plasma ratio BSA Intrinsic Clearance Induction/Inhibition
10 Methods PBPK Model PK simulated in Matlab (R213b) Age, BMI and weight were used to allometrically scale organ weights and cardiac output Physicochemical properties, in vitro apparent permeability, in vitro intrinsic clearance and cytochrome P45 induction were obtained from the literature. TFV Validation (Oral TDF) 5 patients (18-6 years) Simulation of oral 3mg OD 3 Days
11 Methods TDF LA Simulations Screen of 1 patients (18-6 years) Simulation of single injection covering 1 and 3 month Doses 5, 75, 1 and 125mg Release rates ranged from.5 to.2 (h -1 ) Candidate Simulation 5 patients (18-6 years) Monthly injection of 75mg,.2h -1 Quarterly injection of 1mg,.1h -1
12 Results PK Model Validation using results from orally administered TDF 3mg once daily 1 patients 3 days Plasma TFV (ng/ml) Time (h) C max (ng/ml) Cmin (ng/ml) AUC 24 (ngxh/ml) * Clinical Simulated * Clinical Simulated * Clinical Simulated 326 (36.6%) 418 (21.1%) 64.4 (39.4%) 52.2 (44.7%) 3324 (41.2%) 4637 (21.6 %) *VIREAD. Gilead Sciences; 214
13 Results Monthly Injection 75mg,.2h Plasma TFV (ng/ml) TFV-DP (fmol/1 6 cells) Time (Days) Time (days) Plasma Cmax (ng/ml) Plasma Cmin (ng/ml) Plasma AUC (µg x h/ml) (56.37) 34.7 (18.8) 49. (24.67) Intracellular Cmax (fmol/1 6 cells) Intracelluar Cmin (fmol/1 6 cells, 2 Days) Intracelluar Cmin (fmol/1 6 cells, 3 Days) (65.9) 45.9 (16.) (58.74)
14 Results Monthly Injection 75mg,.2h Plasma TFV (ng/ml) TFV-DP (fmol/1 6 cells) Time (Days) Time (days) 1 month Intracelluar Cmin (2 Days) Intracelluar Cmin (3 Days) 5% Reduction (HIV-1) >99 1 9% Reduction (HIV-1) 97.2 >99 99% Reduction (HIV-1)
15 Results Quarterly Injection 1mg,.1h Plasma TFV (ng/ml) TFV-DP (fmol/1 6 cells) Time (days) Time (days) Plasma Cmax (ng/ml) Plasma Cmin (ng/ml) Plasma AUC (µg x h/ml) 88.8 (4.11) 1.5 (4.8) 83.1 (4.41) Intracellular Cmax (fmol/1 6 cells) Intracelluar Cmin (fmol/1 6 cells, 2 Days) Intracelluar Cmin (fmol/1 6 cells, 9 Days) (65.8) 4.7 (14.48) 68.5 (27.15)
16 Results Quarterly Injection 1mg,.1h Plasma TFV (ng/ml) TFV-DP (fmol/1 6 cells) Time (days) Time (days) 3 months Intracelluar Cmin (2 Days) Intracelluar Cmin (9 Days) 5% Reduction (HIV-1) >99 1 9% Reduction (HIV-1) % Reduction (HIV-1)
17 Limitations The simulation of PreP PD assumed that the TFV distribution into key tissues and mucosa is comparable between the traditional oral formulations and intramuscular injections Formulation specific factors not accounted for Concentration cut-offs used were those generated in combination with emtricitabine and are likely to be different for monotherapy
18 Discussion The pharmacokinetics of TFV following intramuscular injection were predicted using a validated in silico modelling approach Simulations indicate sustained concentrations of TFV following monthly and quarterly injections TFV may be a suitable candidate for LA-PrEP, assuming challenges in formulation of LA-TDF can be met These data may be useful to inform development of TDF LA PrEP
19 Discussion Formulation In Vitro Pre-clinical In Vivo Clinical Translation PBPK
20 Acknowledgements University of Liverpool Pharmacology Andrew Owen Marco Siccardi David Back Saye Khoo Neill Liptrott Lee Tatham Darren Moss Owain Roberts Sharon Murphy Rajith Kumar Reddy Rajoli Adeniyi Olagunju Rohan Gurjar Chris David Ana Jimenez-Valverde Christina Chan Louise Tidbury Megan Neary Rana Abutaima Hannah Kinvig Justin Chiong Laura Dickinson Alessandro Schipani Helen Reynolds Kay Seden Henry Pertinez Sara Gibbons Chemistry Steve Rannard James Hobson Johns Hopkins University Charles Flexner Caren L. Freel Meyers David Meyers Amer Al-khouja Funded by 1R1AI grant from the National Institutes of Health
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