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

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) 6.15 3.34 1.7 1.5

Cmin (µg/mL) 2.61 0.83 0.45 0.11

AUC (µg*h/mL) 102 43.4 23 5.84

Tmax (h) 2-4 2 3-4 1.8

T1/2 (h) 17.3 11-12 8.6 9

Protein binding >99% >99%(albumin &

AAG)

>99.4%(albumin >>

AAG)

76-83%(albumin)

Excretion Metabolism;CYP3A

UGT1A1

Metabolism;UGT1A1(major)CYP3A

Metabolism;CYP3A (major)

UGT1A1/3

Metabolism;UGT1A1

High Fat Food Effect (AUC Ratio)

1.24 1.48 1.87 2.1

* Podany AT et al, Clin Pkin 2017; FDA product labels.

Pharmacodynamic Characteristics of INSTIs

Metric Bictegravir Dolutegravir Elvitegravir Raltegravir

IC50 (ng/mL)* 21 16 7.2 NA

IC90 (ng/mL) NA 64 NA NA

IC95 (ng/mL) 162 90 44.9 14.7

EC50 (ng/mL) NA 36 14 NA

EC90 (ng/mL) NA 324 126 NA

IQ (Ctrough/IC95) 16 12 10 8

* Protein-binding corrected.Podany AT et al, Clin Pkin 2017; FDA product labels;Tsiang M, et al. Antimicrob Agents Chemo 2016;60:7086-97; and Gallant JE et al. JAIDS 2017;75:61-66.

Comparative Pharmacodynamic Characteristics of INSTIs and PIs

Drug PB-corrected IQ95(Ctrough / PB-corrected IC95)

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;60:7086-97; Gallant JE et al. JAIDS 2017;75:61-66; FDA product labels; and Acosta EP et al. Antimicrob Agents Chemo 2012;56:5938-45.

Comparative Tablet Sizes of Integrase Inhibitor-Containing Fixed Dose Regimens

Gaur A, et al. Abstract 844, CROI 2018, March 4-7, Boston MA.

ART Regimens Recommended for Initial Therapy in the ARV-Naïve PersonRegimen Components

Integrase InhibitorBased

❖ 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 + TDFa 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.

HIV Viral Suppression Trends: 1997 to 2015

Nance RM, et al. Ann Intern Med 2018; doi:10.7326/M17-2242

Covariate Odds Ratio for Detectable VL

INSTI use 0.54

Age (per decade) 0.76

Hispanic 0.81

Black 1.68

Oral to Injectable Antipsychotic Therapy

Paliperidone Formulation Dose

Oral tablets 3-12 mg/day

Extended release injectable suspension (Sustenna) 39-234 mg once/month

Extended release injectable suspension (Trinza) 273-819 mg every 3 mos

Technology for Drug Delivery

Long-acting depot injections

Subdermal implant

Vaginal rings

Microneedle drug patch

Wearable infusion pump

Novel oral formulations

New drug delivery systems: The promise of long-acting ART

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 Therapeuticconcentration

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

Drug Delivery Options for Antiretrovirals

◼ Long-acting injectables

◼ Implantable devices

◼ Long-acting oral products

◼ Vaginal rings

Cabotegravir and Rilpivirine Concentrations with Parenteral Administration of Long-Acting Suspension

Margolis DA, et al. Lancet 2017;390:1499-1510.

Long-acting Cabotegravir and Rilpivirine for Maintenance Therapy

Margolis DA, et al. Lancet 2017;390:1499-1510.

Long-acting Cabotegravir and Rilpivirine for Maintenance Therapy

Margolis DA, et al. Lancet 2017;390:1499-1510.

A Nanosuspension of Four ARVs: lymphoid tissue targeted therapy

McConnachie LA et al. J Pharm Sci 2018;in press doi.org/10.1016/j.xphs.2018.03.005

Drug Delivery Options for Antiretrovirals

◼ Long-acting injectables

◼ Implantable devices

◼ Long-acting oral products

◼ Vaginal rings

Long-Acting TAF Subdermal Implant

Gunawardana M, et al. Antimicrob Agents Chemother 2015;59:3913-19.

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.

Drug Delivery Options for Antiretrovirals

◼ Long-acting injectables

◼ Implantable devices

◼ Long-acting oral products

◼ Vaginal rings

Recommended ARV Regimens for Initial Therapy in HIV-Infected Children

Lopinavir/Ritonavir Oral Nanoformulationwithout 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: 10.1038/ncomms13184

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 2017. Abstract 39.

Antiretroviral Oral Drug Sustained Release Delivery System

Kirtane A, et al. Nature Communications 2018; 9(2); DOI: 10.1038/s41467-017-02294-6

Antiretroviral Oral Drug Delivery System: application in a swine model

Kirtane A, et al. Nature Communications 2018; 9(2); DOI: 10.1038/s41467-017-02294-6

Drug Delivery Options for Antiretrovirals

◼ Long-acting injectables

◼ Implantable devices

◼ Long-acting oral products

◼ Vaginal rings

Multi-Purpose Implants: vaginal ring for prevention of HIV and contraception

Boyd P, et al. Intl J Pharmaceutics 2016;511:619-29.

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, short-term and chronic concomitant therapy?

◼ How do you manage missed doses?

◼ How do you stop?

◼ How do you manage the long PK tail?

Injectables and Implants – Advantages and Disadvantages

Flexner C. Curr Opin HIV AIDS 2018;13:374-80.

Injectables and Implants – Advantages and Disadvantages

Flexner C. Curr Opin HIV AIDS 2018;13:374-80.

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 (Ct or Cc = Cp)

◼ 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

Thank You