Pharmacodynamics and Drug-Drug Interactions in HCV/HIV Co-Infected Persons on Treatment with DAAs Courtney V. Fletcher, Pharm.D. Dean, College of Pharmacy Professor, Department of Pharmacy Practice and Division of Infectious Diseases University of Nebraska Medical Center
Pharmacokinetics and Pharmacodynamics - Lessons Learned from HIV - Pharmacokinetics matter, Pharmacodynamics (drug concentrations) matter, Resistance matters, Adherence matters, and Convenience and tolerability matters.
Probability (%) Predictive Value of EFV Concentrations for Viral Suppression and CNS Adverse Effects 100 Optimal range Viral suppression 80 60 40 CNS adverse effects 20 0 100 1000 10000 Plasma Efavirenz (ng/ml) Marzolini C, et al. AIDS 2001;15:71-75.
Probability of SVR Probability of Anemia Boceprevir Exposure-Response Relationships Wenning L, Flexner C, et al. AASLD 2012, Abstract 770.
% SVR Hemoglobin Decline and SVR with BOC/PR 80 70 60 50 40 30 20 10 0 1 >1-2 >2-3 >3-4 >4-5 >5 Maximum Hemoglobin Decline During Treatment (g/dl) Sulkowski M, et al. Hepatology 2013;57:974-9
Telaprevir Exposure Response Relationships TVR AUC 24 at 750 q8h = 66,900 ± 26,100 ng*h/ml FDA. Telaprevir NDA Briefing Document.
Telaprevir PK Parameters from q8h and q12h Dosing Parameter Q8h (IFN alfa 2a) N=6 Q12h (IFN alfa 2a) N=10 C min (ng/ml) 2624 ± 507 2134 ± 620 C max (ng/ml) 4523 ± 786 4882 ± 784 AUC (ng*h/ml) 85,890 ± 17,610 81,670 ± 20,090 Marcellin P, et al. Gastroenterology 2011; 40:459-468
Probability of Achieving HIV-RNA < 50cpm as a Function of RAL Trough Conc.* * 800 mg QD arm; stratified by log baseline HIV RNA Rizk ML, et al. Antimicrob Agents Chemother 2012;56:3101-6.
Raltegravir Once vs. Twice Daily Eron JJ, et al. Lancet Infect Dis 2011;11:907-15
SVR12 (%) Highlights of AASLD 2012 clinicaloptions.com/hepatitis OPTIMIZE: Efficacy of Telaprevir BID vs Telaprevir q8h in GT1 HCV Infection SVR12 rates similar with TVR BID and q8h dosing regimens in all subgroups Similar safety and tolerability profile in both treatment arms 100 80 87 92 68 68 65 66 78 81 TVR q8h/pr TVR BID/PR 60 59 58 40 20 0 n/ N = 92/ 106 97/ 105 141/ 208 139/ 206 37/ 57 CC CT TT IL28B GT 38/ 58 209/ 268 213/ 264 61/ 103 61/ 105 F0-2 F3/4 Liver Disease Status Buti M, et al. AASLD 2012. Abstract LB-8. Reproduced with permission.
BOC and TVR Pharmacodynamic Interpretations Within the range of concentrations observed at FDAapproved doses, only weak relationships were observed with SVR. These data suggest usual doses achieve concentrations on the plateau of the exposure SVR-response curve. This suggestion is strengthened for TVR with an equivalent response observed with q8h vs q12h (higher C max, lower C min ) dosing. Higher BOC and TVR exposures were associated with an increased risk of anemia. Intrinsic or extrinsic (e.g. DDIs) that affect BOC or TVR concentrations have the potential to affect HCV response or toxicity.
Do Drug Interactions Matter? HAART, Antiepileptics and HIV Response US Military HIV Natural History Study cohort Use of PI or NNRTI-based regimen for 6 months AED drug use for 28 consecutive days during HAART AEDs grouped as CYP inducers (phenytoin, carbamazepine, or phenobarbital) or other (lamotrigine, levetiracetam, gabapentin). Outcome EI AED (N=19) Other AED (N=85) Odds Ratio Virologic Failure 62.5% 26.7% 4.58 VL < 400 cpm at 6 mos. 33.3% 71.4% 0.20 VL < 400 cpm at 12 mos. 36.4% 75.0% 0.19 Concurrent enzyme inducing AEDs increased the risk of virologic failure and should be avoided. Okulicz J, et al. AIDS Res Ther 2011;8:18.
Drug-Drug Interactions: Management Concepts Some interactions are useful Some interactions can be managed clinically Some interactions are profound, and concomitant administration is contraindicated Some interactions affect both efficacy and toxicity Some interactions have unclear clinical significance
BOC and TVR Pharmacology BOC TVR Metabolic Pathways AKR1C2 + 1C3, CYP3A CYP3A Transporter Pathways In vitro CYP Inhibition In vitro CYP Induction In vitro Transporter Inhibition Effects In vitro Transporter Induction Effects Substrate for P-gp, BCRP CYP3A not CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 or 2E1 Does not induce CYP1A2, 2B6, 2C8, 2C9, 2C19 or 3A P-gp (weak), OATP1B1 & 1B3 Substrate for P-gp CYP3A not CYP1A2, 2C9, 2C19 or 2D6 Low potential to induce CYP2C, 3A or 1A P-gp, OCT1 & 2, MATE1 OATP1B1 & 1B3? (no validated in vitro system) Protein Binding 68-75% 59-76%
BOC and TVR Clinical Pharmacology Evidence for CYP Substrate Inhibition by ketoconazole Induction by efavirenz Evidence for CYP Inhibition Inhibition of midazolam Inhibition of atorvastatin Inhibition of tacrolimus Evidence for P-gp Inhibition Inhibition of digoxin Inhibition of raltegravir Inhibition of TDF BOC + (AUC ratio 2.31) + (AUC ratio 0.81) + (AUC ratio 5.3) + (AUC ratio 2.3) + (AUC ratio 17.1) NA + (AUC ratio 1.04) + (AUC ratio 1.05) TVR + (AUC ratio 1.62) + (AUC ratio 0.74) + (AUC ratio 9.0) + (AUC ratio 7.9) + (AUC ratio 70.3) + (AUC ratio 1.85) + (AUC ratio 1.31) + (AUC ratio 1.30) Evidence for P-gp Induction?? Evidence for Protein Binding Displacement? + (R-methadone)
% Change in BOC or TVR Cmin Effect of RTV-Boosted PIs on BOC and TVR 20 10 ATV/RTV DRV/RTV LPV/RTV 0-10 -20-30 -40-50 -18-15 -35-32 -57-52 -60 Boceprevir Telaprevir
% Change in PI Cmin Effect of BOC and TVR on the RTV-Boosted 100 PIs, ATV, LPV and DRV 80 60 BOC TVR 40 85 20 0 14-20 -40-49 -59-42 -43-60 -80 ATV/RTV DRV/RTV LPV/RTV
Effect of Tipranavir on RTV-boosted Atazanavir, Amprenavir and Saquinavir Walmsley S at al. JAIDS 2008;47:429-40.
Effect of Telaprevir on Methadone TVR (60-76%) and methadone (85%) are bound to plasma proteins, mainly AAG and albumin. TVR reduced R-methadone total concentrations by 30%. Unbound R-methadone, primarily responsible for opioid effect, was unchanged: mean C min 10.63 ng/ml alone and 10.45 ng/ml with TVR. No withdrawal symptoms were observed; no dose adjustment is necessary when initiating TVR; close monitoring still recommended. van Heeswijk R, et al. EASL 2011. Abstract 654.
BOC and TVR with Etravirine and Rilpivirine Combination Effect and Recommendation BOC + ETR 1 ETR: AUC and Cmin 25% BOC: AUC 10%; Cmin 12% Rec: Combination not recommended TVR + ETR 2 ETR: AUC and Cmin 6% TVR: AUC 16%; Cmin 25% Rec: Insufficient data for dose recommendation (FDA, Feb 27); avoid coadministration at this time. BOC + RPV 3 RPV: AUC 39%; Cmin 51% BOC: AUC 6%; Cmin 4% Rec: Coadministration should be OK (CVF). TVR + RPV 2 RPV: AUC 78%; Cmin 93% TVR: AUC 5%; Cmin 11% Rec: Potential for RPV-associated QTc prolongation; insufficient data for recommendation; avoid coadministration at this time (CVF). 1. Hammond K, et al. JAIDS 2013;62:67-73. 2. Kakuda TN, et al. 13 th International HIV Clinical Pharmacology Workshop. Barcelona, Spain, April 2012. Abstract O-18. 3. Rhee E, et al. CROI 2013. Abstract 537.
Plasma and Intracellular Interactions with Ribavirin (RBV) Combination Abacavir and RBV 1 Effect and Recommendation Plasma RBV concentrations no different when RBV given alone or with ABC. Intracellular RBV-triphosphate concentrations also not different. No evidence for an interaction between ABC and RBV. Telaprevir and RBV 2 Dose adjusted RBV plasma concentrations were 1.54 higher in HCV-infected persons receiving TPV + PR vs PR only. Intracellular RBV-MP, DP and TP concentrations in PBMCs were 2.5, 3 and 2-fold higher in TVR + PR vs. PR only. Increased plasma and intracellular RBV exposure may contribute to the increased rates of anemia seen with TVR and RBV-containing HCV therapy. 1. Andrade A, et al. CROI 2013. Abstract 538. 2. Hammond K, et al. CROI 2013. Abstract 34.
Some Interesting Interaction Data from AASLD 2012 Combination TVR and levothyroxine 1 BOC and ethinyl estradiol norethindrone 2 BOC or TVR with CSA or TAC 3,4,5,6,7 Effect and Recommendation 4 patients treated with levothyroxine had increased TSH after the start of TVR, which returned to normal after TVR stopped. Mechanism uncertain; more data needed; monitor. AUC and Cmax of EE decreased 26% and 21%, respectively. Cmax of NE decreased 17%. As long as at least 1 mg of NE, interaction unlikely to be clinically significant (FDA label 02/15/13). 5 abstracts describing CSA and TAC dosing in presence of BOC or TVR. CSA dose reductions were from 0.5 to 1.5-fold reduction with BOC, and up to 2.8-fold with TVR. TAC dose reductions were 6-fold for BOC and 25 to 40-fold with TVR. Collectively provides evidence these interactions may be manageable with close monitoring. 1. Abstract 1845. 2. Abstract 1901. 3-7. Abstracts 9, 10, 208, 209, 720. AASLD Annual Meeting, Nov 2012. Boston.
The Future of HIV and HCV Drug-Drug Interactions Combination Sofosbuvir and CSA or TAC 1 Sofosbuvir and TDF/FTC/EFV, RPV, DRV/RTV and RAL 2 Sofusbuvir + ledipasvir + RBV 3 Effect CSA, 2% decrease in AUC. TAC, 9% increase in AUC. No clinically relevant interaction. HIV: TFV Cmax increased 25%; RAL AUC decreased 27%. SOF: Cmax decreased 20% with TDF/FTC/EFV; RPV, DRV/RTV, RAL increased AUC 21-45% but no effect on major metabolite (GS-331007). No evidence for clinically relevant interactions. Well tolerated and achieved potent antiviral suppression, with a 100% SVR-12 in treatment-naïve (25/25) and experienced (9/9) HCV GT1 persons. 1. Abstract 1869; 2. Abstract 1877. AASLD, Nov 2012. Boston. 3. Abstract 41LB, CROI 2013. Atlanta.
TVR Dynamics Where Does the Risk of Virologic Failure Increase? TFV PK with EFV Parameter TVR (750 q8h + EFV) Cmax (ng/ml) 2297 ± 627 ( 9%) Cmin (ng/ml) 745 ± 352 ( 47%) AUC 24 of 34,500. Where is the inflection point off the plateau phase? AUC 8 (ng*h/ml) 11,523 ± 3663 ( 26%) EFV reduces TVR conc; AUC decrease is 26%. With EFV, expected AUC 24 is 34,570 ± 11,062 ng*h/ml, which is an exposure range less than achieved with TVR usual dose. An increased dose of TVR to 1125 mg q8h is recommended to manage this drug interaction.
SVR24 (%) Highlights of AASLD 2012 clinicaloptions.com/hepatitis Study 110: SVR24 With TVR + PegIFN/RBV in HCV GT1/HIV-Coinfected Patients Higher SVR24 rate with TVR-based therapy 100 80 60 40 20 n/n = 0 74 71 69 28/ 38 45 10/ 22 5/ 7 33 2/ 6 11/ 16 Telaprevir + PR Placebo + PR Sulkowski MS, et al. AASLD 2012. Abstract 54. Reproduced with permission. 80 50 50 4/ 8 12/ 15 4/ 8 TVR plasma levels similar in patients with or without ART TVR dose increased to 1125 q8h if given with EFV EFV and ATV/RTV plasma levels similar in patients with or without TVR No HIV breakthroughs in patients using ART during HCV treatment Safety and tolerability similar to treatment in patients with HCV monoinfection
Clinical Significance of Drug-Drug Interactions The clinical significance of a drug-drug interaction can only be determined or confirmed through a clinical study. In the absence of (or pending) clinical trial data, well defined exposure-response data provide a basis to predict the significance of a drug-drug interaction; however, there will be settings where the existing data are not informative as to PK and PD of the interaction. Exercise a measure of caution in managing drug interactions where no confirmatory clinical data exist.
Drug Interaction Resources hivinsite.ucsf.edu Updated drug interaction database with references and interactive tool to assess drug interactions. www.aidsinfo.nih.gov DHHS Guidelines for use of antiretroviral agents and updated drug interaction tables. www.hiv-druginteractions.org www.hep-druginteractions.org Downloadable drug interaction charts; interactive tools to assess interactions; updated news on published abstracts and papers www.hivmedicationguide.com Interactive drug interaction database Micromedex: comprehensive drug database (subscription required); an app is available
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EXTRAs
Clinical Pharmacology Major goals in clinical pharmacology are to describe, quantitate and predict drug effects in humans. Pharmacokinetics: the time course of a drug in humans Pharmacodynamics: relationships between the dose or concentration of drug in the body (exposure) and measured effects Pharmacogenetics: relationships among discrete inherited traits related to drug absorption and disposition, and response
Drug Interactions Occur when either the pharmacokinetics or the pharmacodynamics of one drug is altered by another are a source of variability in drug response are graded responses, that are dependent upon the concentration of the interacting species, and on dose and time pharmacokinetic interactions may affect absorption rate, availability, distribution, and hepatic or renal clearance pharmacodynamic interactions may be antagonistic, synergistic, or additive
% Change in BOC, TVR or TDF Cmin Effect of RTV-Boosted PIs on Boceprevir, Telaprevir and Tenofovir 60 40 ATV/RTV DRV/RTV LPV/RTV 20 22 37 51 0-20 -18-15 -35-32 -57-52 -40-60 Boceprevir Telaprevir Tenofovir