12/13/19 HIV Pharmacology Parya Saberi, PharmD, MAS, AAHIVP Associate Professor, UCSF Center for AIDS Prevention Studies The Medical Management of HIV and Hepatitis December 2019 1 Disclosure • I have nothing to disclose 2 P. Saberi, PharmD, MAS 1
12/13/19 Objectives 1. List ARV medications & examine their mechanisms of action. 2. Review pharmacology basics. 3. Examine dose, adverse effects, drug interactions, & special considerations of ARVs in recommended regimens. 4. Review ART regimens & tailoring. 3 FDA-approved ARVs Nucleoside Reverse Transcriptase Inhibitors Fusion Inhibitors Enfuvirtide (ENF): Fuzeon Abacavir (ABC): Ziagen Emtricitabine (FTC): Emtriva Protease Inhibitors Lamivudine (3TC): Epivir Tenofovir (TDF): Viread Atazanavir (ATV): Reyataz Zidovudine (ZDV): Retrovir Darunavir (DRV): Prezista Fosamprenavir (Fos-APV): Lexiva Non-nucleoside Reverse Transcriptase Inhibitors Ritonavir (RTV): Novir Doravirine (DOR): Pifeltro Tipranavir (TPV): Aptivus Efavirenz (EFV): Sustiva Etravirine (ETR): Intelence Pharmacokinetic Enhancers Nevirapine (NVP & NVP XR): Viramune Cobicistat (COBI): Tybost Rilpivirine (RPV): Edurant Post-Attachment Inhibitors Integrase Inhibitors Ibalizumab (IBA): Trogarzo Bictegravir (BIC): - Dolutegravir (DTG): Tivicay CCR5 Co-receptor Antagonists Elvitegravir (EVG): Vitekta Raltegravir (RAL): Isentress Maraviroc (MVC): Selzentry 4 P. Saberi, PharmD, MAS 2
12/13/19 Fixed Dose Combinations Combination ARVS Single Pill Regimens ABC/3TC (Epzicom) BIC/TAF/FTC (Biktarvy) ABC/ZDV/3TC (Trizivir) CAB/RPV (Cabenuva) ATV/c (Evotaz) DTG/ABC/3TC (Triumeq) DRV/c (Prezcobix) DTG/3TC (Dovato) LPV/r (Kaletra) DTG/RPV (Juluca) TAF/FTC (Descovy) DOR/TDF/3TC (Delstrigo) TDF/FTC (Truvada) DRV/c/TAF/FTC (Symtuza) TDF/3TC (Cimduo) EFV/TDF/FTC (Atripla) ZDV/3TC (Combivir) EFV/TDF/3TC (Symfi) EVG/c/TDF/FTC (Stribild) EVG/c/TAF/FTC (Genvoya) RPV/TDF/FTC (Complera) RPV/TAF/FTC (Odefsey) 5 HIV Life-cycle Fusion Inhibitors CCR5 Co- receptor Protease Inhibitors Inhibitors Reverse Transcriptase Inhibitors Integrase Inhibitors 6 P. Saberi, PharmD, MAS 3
12/13/19 Recommended Initial Regimens for Most People with HIV (regimens with durable virologic efficacy, favorable tolerability & toxicity profiles, & ease of use) DTG DTG BIC 3 RAL ABC/3TC 2 TDF/FTC or TAF/FTC 1 1 TDF/FTC not recommended if CrCl <60 mL/min & TAF/FTC not recommended if CrCl <30 2 If HLA-B*5701 is negative 3 Part of the “Recommended Initial Regimen“ when used with TAF/FTC http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf 7 Recommended Initial Regimens in Certain Clinical Situations (Effective & tolerable regimens, but some disadvantages vs. regimens listed previously, or less supporting data from RCTs. However, may be preferred in certain clinical situations.) EVG/c DRV/r DRV/c DRV/c ATV/c ATV/r DRV/r DRV/r RPV 3 DOR RAL 4 DTG EFV ABC/3TC 2 3TC TDF/FTC or TAF/FTC 1 1 TDF/FTC not recommended if CrCl <70 & TAF/FTC not recommended if CrCl <30 2 If HLA-B*5701 is negative 3 If pre-treatment HIV RNA <100,000 copies/mL & CD4 >200 cells/mm 3 4 If HIV RNA <100,000 copies/mL http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf 8 P. Saberi, PharmD, MAS 4
12/13/19 Lightening Fast Pharmacology Review 9 Pharmacology Review • PK – What your body does to the drug – Study & characterization of time course of drug Absorption, Distribution, Metabolism, & Excretion • PD – What the drug does to your body – Subjective (anxiety level) or objective (BP, pupil size) 10 P. Saberi, PharmD, MAS 5
12/13/19 EXCRETION 11 Transporters • P-glycoprotein (P-gp): efflux enzyme that “pushes” drugs out of GI blood stream back into GI lumen – P-gp inhibitor: RTV, COBI – P-gp inducer: SJW, GFJ, rifampin • Organic Anion Transporters (OAT) & Organic Cation Transporters (OCT): involved in drug secretion or reabsorption; in kidneys, brain, liver, skeletal muscle, heart, small intestine, prostate, … – OAT inhibitor: COBI, RTV – OCT inhibitor: RTV, DTG • Multidrug & Toxin Extrusion (MATE) Transporter: role in renal & biliary excretion of organic cations; involved in tubular secretion of Cr; in liver, kidneys, … – MATE inhibitor: RTV, COBI, DTG • Breast Cancer Resistance Protein (BCRP): role in drug disposition & tissue protection; in small intestine, liver, kidneys, & blood-brain barrier – BCRP inhibitor: RTV, COBI 12 P. Saberi, PharmD, MAS 6
12/13/19 METABOLISM 13 Uridine Diphospho- Glucuronosyltransferase (UGT) • Responsible for glucuronidation, a major part of metabolism (conjugation) – UGT 1A1 Substrate: RAL, DTG – UGT 1A1 Inhibitor: ATV – UGT 1A1 Inducer: RTV, rifampin 14 P. Saberi, PharmD, MAS 7
12/13/19 Cytochrome P450 Enzymes • Essential for metabolism of 2/3 of meds cleared by metabolism – >50 enzymes; however, 6 metabolize 90% of drugs: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 , & CYP3A5 • Primary cause of majority of drug-drug & drug-food interactions • CYP450 Inducers : ↑CYP450 enzyme activity by ↑enzyme synthesis (e.g., EFV, rifampin) • CYP450 Inhibitors : Block metabolic activity of CYP450 enzymes (e.g., PIs) 15 Question #1: How quickly does CYP450 induction occur? 1. 1-2 hours 2. 1-2 days 3. 1-2 weeks 4. 1-2 months 16 P. Saberi, PharmD, MAS 8
12/13/19 CYP450 Inducers • Onset gradual ( 1-2 weeks ) • Onset depends on half-life (t 1/2 ) of inducer & synthesis of new enzymes • Offset depends on inducer elimination & decay of enzyme stores 17 Question #2: How quickly does CYP450 inhibition occur? 1. 1-2 hours 2. 1-2 days 3. 1-2 weeks 4. 1-2 months 18 P. Saberi, PharmD, MAS 9
12/13/19 CYP450 Inhibitors • Onset is rapid (after 1-2 doses) • Extent of inhibition depends on dose & binding ability of inhibitor • Offset depends on elimination of inhibitor & half-life of the inhibitor at enzyme site • All PIs are net inhibitors of CYP3A4 – Boosting: use of low-dose CYP450 inhibitor to ↑ARV exposure 19 Boosting • Taking advantage of a drug-drug interaction • Low-dose CYP450 inhibitors (e.g., RTV or COBI) lead to: – ↑AUC, ↑Cmin & ↑Cmax • ↓ risk of drug resistance • Can use lower doses of PI • May eliminate food restriction – ↑plasma half-life ( t 1/2 ) • ↓dosing frequency Zeldin RK, et al. Journal of Antimicrobial Chemotherapy.53.2004. 20 P. Saberi, PharmD, MAS 10
12/13/19 Drawbacks of Boosting • ↑ potential of other drug-drug interactions • ↑ risk of metabolic AEs Important to note that • Boosting with RTV or COBI is recommended for PI- & EVG-based regimens 21 Question #3: Which of the following is (are) true re: RTV & COBI? 1. Both inhibit P-gp & BCRP transporters 2. Both inhibit MATE & OAT transporters 3. Both result in increased Scr & TG 4. Both inhibit or induce CYP450 enzymes 5. Options 1, 2, & 3 6. Uhhh… What? 22 P. Saberi, PharmD, MAS 11
12/13/19 RTV vs COBI RTV COBI (Structural analogue of RTV) Boosting w/ 100mg QD-BID Boosting w/ 150mg QD Inhibits or induces drug- Inhibits drug-metabolizing metabolizing enzymes → DDIs enzymes → DDIs Similar AE profile: N/D, HA, nasopharyngitis, ↑TG, TC, ↑SCr, ↓CrCl Marzolini C, et al. J Antimicrob Chemother. 2016. Tseng A, et al. Ann Pharmacother. 2017. 23 RTV vs COBI: PK RTV COBI Absorption Both inhibit intestinal transporters P-gp & BCRP: ↑absorption of TDF , TAF , ATV, DRV - ↑AUC of TDF by 25-37% when w/ boosted ARV regimen - TAF dose= 25mg w/ unboosted regimens; 10mg w/ boosted regimens Marzolini C, et al. J Antimicrob Chemother. 2016. Tseng A, et al. Ann Pharmacother. 2017. 24 P. Saberi, PharmD, MAS 12
12/13/19 RTV vs COBI: PK RTV COBI Absorption Both inhibit intestinal transporters P-gp & BCRP: ↑absorption of TDF , TAF , ATV, DRV - ↑AUC of TDF by 25-37% when w/ boosted ARV regimen - TAF dose= 25mg w/ unboosted regimens; 10mg w/ boosted regimens Excretion Both inhibit OAT & MATE: • ↑Scr due to inhibition of Cr secretion vs. impairment of renal function • COBI results in higher Scr vs. RTV; may be due to COBI accumulating in tubular cells & having higher concentrations to inhibit MATE Marzolini C, et al. J Antimicrob Chemother. 2016. Tseng A, et al. Ann Pharmacother. 2017. 25 RTV vs COBI: PK Interchangeable as CYP3A inhibitors Metabolism RTV COBI Inhibition • CYP3A inhibitor • More specific CYP3A • CYP2D6, CYP2C19, inhibitor CYP2C8, & CYP2C9 • Weaker CYP2D6 inhibitor inhibitor Induction • CYP1A2, CYP2B6, • Unlikely to induce drug CYP2C9, CYP2C19, & metabolism (CYP or UGT) UGT inducer Marzolini C, et al. J Antimicrob Chemother. 2016. Tseng A, et al. Ann Pharmacother. 2017. 26 P. Saberi, PharmD, MAS 13
12/13/19 RTV vs COBI: DDIs Summary of differences in predicted interaction profiles: Meds that are… RTV COBI Examples Only glucuronidated ↓ not affected Bupropion or Methadone Glucuronidated &/or metabolized ↓ moderately ↑ Sertraline by inducible CYPs > CYP3A CYP substrate ↓ or ↑ only ↑ Duloxetine • Inducible CYPs: CYP1A2, CYP2B6, CYP2C9, & CYP2C19 • ELV: inducer of CYP2C9 (ELV/c overall effect: ↓warfarin) Marzolini C, et al. J Antimicrob Chemother. 2016. Tseng A, et al. Ann Pharmacother. 2017. 27 Protease Inhibitors 28 P. Saberi, PharmD, MAS 14
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