Pharmacologic Characteristics and Delivery Options for Integrase Inhibitors

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1 Pharmacologic Characteristics and Delivery Options for Integrase Inhibitors Courtney V. Fletcher, Pharm.D. Dean, College of Pharmacy Professor, Department of Pharmacy Practice and Division of Infectious Diseases University of Nebraska Medical Center

2 Pharmacokinetic Characteristics of INSTIs PK Parameter Bictegravir (50 mg/day) Dolutegravir (50 mg/day) Elvitegravir (150 mg/day) Raltegravir (400 mg BID) Cmax (µg/ml) Cmin (µg/ml) AUC (µg*h/ml) Tmax (h) T1/2 (h) Protein binding >99% >99% (albumin & AAG) Excretion High Fat Food Effect (AUC Ratio) Metabolism; CYP3A UGT1A1 Metabolism; UGT1A1 (major) CYP3A >99.4% (albumin >> AAG) Metabolism; CYP3A (major) UGT1A1/ % (albumin) Metabolism; UGT1A * Podany AT et al, Clin Pkin 2017; FDA product labels.

3 Pharmacodynamic Characteristics of INSTIs Metric Bictegravir Dolutegravir Elvitegravir Raltegravir IC 50 (ng/ml)* NA IC 90 (ng/ml) NA 64 NA NA IC 95 (ng/ml) EC 50 (ng/ml) NA NA EC 90 (ng/ml) NA NA IQ (C trough /IC 95 ) * Protein-binding corrected. Podany AT et al, Clin Pkin 2017; FDA product labels; Tsiang M, et al. Antimicrob Agents Chemo 2016;60: ; and Gallant JE et al. JAIDS 2017;75:61-66.

4 Comparative Pharmacodynamic Characteristics of INSTIs and PIs Drug PB-corrected IQ 95 (Ctrough / PB-corrected IC 95 ) Integrase Inhibitors Bictegravir (50 mg once daily) 16 Dolutegravir (50 mg once daily) 12 Elvitegravir (150 mg once daily) 10 Raltegravir (400 mg twice daily) 8 Protease Inhibitors Atazanavir/RTV (300/100 once daily) 13 Darunavir/RTV (800/100 once daily) 85 Podany AT et al, Clin Pkin 2017; Tsiang M, et al. Antimicrob Agents Chemo 2016;60: ; Gallant JE et al. JAIDS 2017;75:61-66; FDA product labels; and Acosta EP et al. Antimicrob Agents Chemo 2012;56:

5 Comparative Tablet Sizes of Integrase Inhibitor-Containing Fixed Dose Regimens Gaur A, et al. Abstract 844, CROI 2018, March 4-7, Boston MA.

6 ART Regimens Recommended for Initial Therapy in the ARV-Naïve Person Regimen Integrase Inhibitor Based Components BIC/FTC/TAF 1 tablet daily DTG/ABC/3TC 1 tablet daily only if HLA-B*5701 negative DTG + FTC + TDF or TAF 2 tablets daily EVG/COBI/FTC + TDF a or TAF (1 tablet daily) ( a only if pre-art CrCl > 70 mls/min) RAL + FTC + TDF or FTC (2 tablets AM and 1 PM) Abbreviations: BIC, bictegravir; FTC, emtricitabine; TAF, tenofovir alafenamide; DTG, dolutegravir; ABC, abacavir; 3TC, lamivudine; TDF, tenofovir disoproxil fumarate; EVG, elvitegravir; COBI, cobicistat; RAL, raltegravir.

7 HIV Viral Suppression Trends: 1997 to 2015 Covariate Odds Ratio for Detectable VL INSTI use 0.54 Age (per decade) 0.76 Hispanic 0.81 Black 1.68 Nance RM, et al. Ann Intern Med 2018; doi: /m

8 Oral to Injectable Antipsychotic Therapy Paliperidone Formulation Oral tablets Extended release injectable suspension (Sustenna) Extended release injectable suspension (Trinza) Dose 3-12 mg/day mg once/month mg every 3 mos

9 Technology for Drug Delivery Long-acting depot injections Microneedle drug patch New drug delivery systems: The promise of long-acting ART Novel oral formulations Subdermal implant Wearable infusion pump Vaginal rings

10 Characteristics of Successful Long-Acting Agents Most developed from oral formulations Low oral dose Medium to long half life Therapeutic concentrations must be low Drug development strategies to improve these characteristics: nanoformulations; prodrugs; devices Daily oral dose Half life Therapeutic concentration DMPA 10 mg 17 h pg to ng range Risperidone 3 mg 20 h 1-5 μg/ml Cabotegravir 30 mg 14 h 1.5 μg/ml Rilpivirine 25 mg 50 h 100 ng/ml

11 Drug Delivery Options for Antiretrovirals Long-acting injectables Implantable devices Long-acting oral products Vaginal rings

12 Cabotegravir and Rilpivirine Concentrations with Parenteral Administration of Long-Acting Suspension Margolis DA, et al. Lancet 2017;390:

13 Long-acting Cabotegravir and Rilpivirine for Maintenance Therapy Margolis DA, et al. Lancet 2017;390:

14 Long-acting Cabotegravir and Rilpivirine for Maintenance Therapy Margolis DA, et al. Lancet 2017;390:

15 A Nanosuspension of Four ARVs: lymphoid tissue targeted therapy McConnachie LA et al. J Pharm Sci 2018;in press doi.org/ /j.xphs

16 Drug Delivery Options for Antiretrovirals Long-acting injectables Implantable devices Long-acting oral products Vaginal rings

17 Long-Acting TAF Subdermal Implant Gunawardana M, et al. Antimicrob Agents Chemother 2015;59:

18 EFdA Shows Prolonged Release After Parenteral Administration > 180 day release from a solid formulation after single injection in the rat. Ongoing non-human primate study suggests implants can deliver sustained therapeutic plasma and intracellular concentrations.

19 Drug Delivery Options for Antiretrovirals Long-acting injectables Implantable devices Long-acting oral products Vaginal rings

20 Recommended ARV Regimens for Initial Therapy in HIV-Infected Children

21 Lopinavir/Ritonavir Oral Nanoformulation without Alcohol The LPV/RTV commercial solution contains 42.4% (v/v) ethanol and 15.3% (v/v) propylene glycol. Warning against use in premature babies because of risk of serious adverse effects. Plasma LPV concentrations when LPV/RTV (4:1 ratio) was given orally in the conventional vs. spray-dried nanoparticle formulation without ethanol or propylene glycol to rats. Giardiello M et al. Nature Communications 2016; doi: /ncomms13184

22 Efavirenz Solid Nanoparticle with Enhanced Oral Bioavailability EFV solid drug nanoparticle given to healthy volunteers and comparted with the conventional 600 mg EFV dose. A 300 mg dose of the nanoparticle was predicted to be bioequivalent to 600 mg conventional, except for C24, which was higher with the nanoparticle. The nanoparticle formulation has the potential to achieve therapeutic equivalence with a 50% dose reduction, and to achieve a significant cost and manufacturing savings. Owen A. CROI Abstract 39.

23 Antiretroviral Oral Drug Sustained Release Delivery System Kirtane A, et al. Nature Communications 2018; 9(2); DOI: /s

24 Antiretroviral Oral Drug Delivery System: application in a swine model Kirtane A, et al. Nature Communications 2018; 9(2); DOI: /s

25 Drug Delivery Options for Antiretrovirals Long-acting injectables Implantable devices Long-acting oral products Vaginal rings

26 Multi-Purpose Implants: vaginal ring for prevention of HIV and contraception Boyd P, et al. Intl J Pharmaceutics 2016;511:

27 Long-acting injectables work now what? Who is the best candidate for LA administration, for therapy, for prevention? And, what about children, adolescents, pregnant women? Oral lead in what, how long, can it be eliminated? What is the optimal LA dose and frequency and evidence for that that meets regulatory purposes? Can injection volumes be reduced? How do you manage toxicities, acute and long term? How do you manage potential drug-drug interactions, shortterm and chronic concomitant therapy? How do you manage missed doses? How do you stop? How do you manage the long PK tail?

28 Injectables and Implants Advantages and Disadvantages Flexner C. Curr Opin HIV AIDS 2018;13:

29 Injectables and Implants Advantages and Disadvantages Flexner C. Curr Opin HIV AIDS 2018;13:

30 Novel ARV Drug Delivery: needs and some opportunities to improve patient care Long acting Nanoformulated injectables and implants to achieve sustained (one month, three months) drug delivery Targeted delivery Nanoformulated injectables and implants to achieve improved tissue/organ distribution such as to brain and lymphoid tissues (C t or C c = C p ) New drugs Highly potent, selective agents with novel mechanisms of action and additive-to-synergistic with existing agents Pediatric formulations and fixed dose combinations: New formulations and combinations; nanoformulations

31 Thank You