Pharmacokinetic-guided Antiretroviral Therapy. Chih-Hsun Tai, M.S., RPh. Department of Pharmacy National Taiwan University Hospital

Transcription

1 Pharmacokinetic-guided Antiretroviral Therapy Chih-Hsun Tai, M.S., RPh. Department of Pharmacy National Taiwan University Hospital

2 Introduction HAART allows a complete viral suppression But Not all patients respond optimally Inadequate adherence Intolerance Viral resistance Insufficient drug concentration Therapeutic Drug Monitor HAART: highly active antiretroviral therapy

3 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV Panel s Recommendations Therapeutic drug monitoring (TDM) for antiretroviral agents is not recommended for routine use in the management of patients with HIV (BII). TDM may be considered in selected clinical scenarios. Rating of Recommendations: A = Strong; B = Moderate; C = Optional Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion

4 Which? Who? When?

5 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV Who When Among pregnant women who have risk factors for virologic failure, physiologic changes may result in reduced drug exposure during the later stages of pregnancy and thus further increase the risk of virologic failure Heavily pretreated patients experiencing virologic failure and who may have viral isolates with reduced susceptibility to ARVs Failure to achieve expected virologic response in medication-adherent patients. Suspicion of clinically significant drug-drug or drug-food interactions that may result in reduced efficacy or increased dose-related toxicities Changes in pathophysiologic states that may impair gastrointestinal, hepatic, or renal function, thereby potentially altering drug absorption, distribution, metabolism, or elimination Use of alternative dosing regimens and ARV combinations for which safety and efficacy have not been established in clinical trials Concentration-dependent, drug-associated toxicities

6 Which ARV? Well-known exposure-response relationship Established therapeutic range Efficacy Safety Availability of accurate test Wide interpatient variability Current Opinion in Virology 2016, 18:50 56

7 Factors influence ARV s Interpatient Variability Drug-drug interactions Drug-food interations Age, gender, ethnicity Disease status Pregnancy Genetic differences Current Opinion in Virology 2016, 18:50 56

8 Pharmacokinetics Clin Pharmacokinet Apr;56(4):

9 Main genetic factors associated with anti-hiv drugs. Drug Abacavir Lamivudine Tenofovir diphospate Efavirenz Etravirine Nevirapine Atazanavir Ritonavir Maraviroc Raltegravir Elvitegravir Individualization factors HLA-B*57:01 genetic test associated with hypersensitivity reaction MRP4 gene SNPs associated with higher intracellular concentrations ABCC2, ABCC4, ABCC10 and SLC28A2 gene SNPs affect plasma/intracellular concentrations and renal toxicity CYP2B6, CYP2D6, CYP3A4, CYP2A6, UGT2B7, NR1I3 and ABCB1 gene SNPs related to drug pharmacokinetics and neuropsychiatric intolerance CYP2C9 and CYP2C19 gene polymorphisms affect drug clearance CYP2B6, CYP3A5, CYP3A4, ABCB1 and ABCC10 gene variants related to plasma exposure and treatment outcome ABCB1, CYP2B6, HLADRB1*0101, HLACV8 and HLAB14SNPs associated with hepatotoxicity and hypersensitivity reactions CYP3A5, ABCB1, SLCO1B1 and NR1I2 associated with pharmacokinetics ABCB1 and UGT1A1 association with hyperbilirubinemia CYP3A4 and OTAP1B1 related to lower clearance SLCO1B1 and CYP3A5 SNPs association with pharmacokinetics ABCB1, UGT1A9 and UGT1A1 gene polymorphisms association with drug plasma exposure ABCB1 associated with virological failure ABCG2 and HNF4 gene variants association with CSF drug concentrations UGT1A1 gene variants associated with drug clearance Pharmacogenomics Jan;19(2):

10 Description of tissue expression and potential effects of selected enzymes involved in the disposition of antiretrovirals Enzyme Gene Highest tissue expression CYP CYPs Ubiquitous with tissue-specific differences UGTs UGTs Ubiquitous, most isoforms in the liver and gut P-gp ABCB1 Ubiquitous, on the surface of several cells OATP1B1 SLCO1B1 Liver (hepatocyte membrane) PXR NR1I2 Ubiquitous (intranuclear) Potential effect of decreased function/expression Reduced metabolism with higher plasma concentrations, potential use of alternative metabolic pathways Reduced metabolism and drug excretion, higher plasma concentrations Increased intestinal absorption, higher intracellular concentrations, higher tissue distribution (including the central nervous system) Reduced hepatic uptake, higher plasma and lower hepatic concentrations Mutated gene with gain of function and therefore higher expression of transporter and metabolizing enzymes; lower plasma concentrations ARVs with confirmed PK/PG association CYP2B6: efavirenz, nevirapine None None None NR1I2: atazanavir Clin Pharmacokinet Apr;56(4):

11 Trough Concentrations of Antiretroviral Drugs for Patients Who Have Drug-Susceptible Virus (1 mg/l) Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. p H-19 (2014 version)

12 ENCORE 1 study A randomised, double-blind, placebo-controlled, non-inferiority trial, 38 clinical sites in 13 countries To compare the safety and efficacy of EFV (400 mg vs 600 mg) in treatment-naive HIV-infected adults Randomisation* 1 : 1 Double-blind W48 W96 ARV-naïve PVL > 1,000 cp/ml CD4 cell count: /mm 3 N = 324 N = 312 TDF/FTC + EFV 400 mg (2 x 200 mg pills + 1 placebo pill) QD TDF/FTC + EFV 600 mg (3 x 200 mg pills) QD *Randomisation was stratified by clinical site and by HIV RNA (< or > 100,000 c/ml) at screening Lancet Apr 26;383(9927):

13 ENCORE 1 study 400 mg EFV+TDF/FTC is non-inferior to 600 mg EFV+TDF/FTC during 48 weeks in ART-naive adults with HIV1 infection (94 1% vs 92 2%, p=0.36)

14 ENCORE 1 study Study drug-related adverse events were significantly more frequent in the 600 mg group than in the 400 mg group (146 [47%] vs 118 [37%]), p=0 01)

15 Pharmacokinetic Studies In NTUH

16 Efavirenz Objectives: to investigate the effects of CYP2B6 G516T polymorphisms and concomitant RIF use on the plasma EFV conc. in HIV-infected Taiwanese. Study period: October 2009 to August 2012 Include: Pt > 18 y/o with EFV(600 mg) based cart >14 days Also include patient infected with TB and treated with RIF based regimen Data collection: demographic data, CD4 counts, PVL, HBV/HCV status, concomitant drugs etc. Lab investigations EFV conc(c12).: samples were collected 12±1 hrs after the last dose CYP2B6 genotyping cart ombination antiretroviral therapy PLoS One Feb 14;9(2):e88497

17 Efavirenz Clinical characteristics of 171 HIV-infected patients. 66.1% 32.2% 1.8% PLoS One Feb 14;9(2):e88497

18 Efavirenz Clinical characteristics of 171 HIV-infected patients. PLoS One Feb 14;9(2):e88497

19 Efavirenz EFV conc. of HIV p ts with and without taking RIF EFV conc. of 171 HIV p'ts with different genotypes(cyp2b6 G516T) PLoS One Feb 14;9(2):e88497

20 Efavirenz Univariate and multivariate logistic regression analyses of variables associated with toxic EFV conc. > 4 mg/l PLoS One Feb 14;9(2):e88497

21 Efavirenz Methods: April 2013 to June 2014 For those with EFV C12 >2.0 mg/l, EFV was reduced to 0.5tab QD. EFV C12 were repeated 4-12 weeks after switch. CYP2B6 G516T polymorphisms were determined. Results: 111 pts (95.5% male; 96.4% with PVL <40 copies/ml) included. 45.5% of them had CYP2B6 GT or TT genotypes 32.4% weighed 60 kg or less. The mean baseline EFV C12 before switch was 3.65 mg/l (IQR, ) for 111 pts, which decreased to 1.96 mg/l (IQR, ) for 64 pts who had completed follow-up of C12 EFV 4 weeks after switch. A reduction of 49.4% (IQR, %) was observed. As of 10 July, 2014, all of the 38 pts who had completed at least one follow-up of PVL achieved undetectable PVL (<40 copies/ml) after a mean observation of 13 weeks (IQR, 7-15 weeks). J Int AIDS Soc Nov 2;17(4 Suppl 3):19524.

22 Efavirenz Subsequent analysis

23 Efavirenz Objectives: To investigate the predictors of mid-dose EFV conc.(c12) > 2 mg/l in HIV-infected Taiwanese. Study period: October 2009 to July Pts Results: Plasma EFV conc. in (a) weight quartile groups and 14: wrong time 27: RIF/AED/PI 5: poor adherence (b) 10-kg increment groups. 456 Pts Included Sci Rep Nov 23;7(1):16187.

24 Efavirenz Predictors of plasma mid-dose efavirenz concentrations in the analysis of covariance (ANCOVA) models. a) The model with CYP2B6 516G>T polymorphism b) The model without CYP2B6 516G>T polymorphism. Parameter Estimate 95% Confidence Limits p-value a) Intercept < CYP2B6 516G>T genotype GG 0 GT < TT < Weight (per 10-kg increase) < b) Intercept < Weight (per 10-kg increase) < Sci Rep Nov 23;7(1):16187.

25 Efavirenz Predicted probability of plasma mid-dose efavirenz concentrations 2 mg/l in different weights by binary logistic regression model. Weight 58 kg provided better predictabilities for efavirenz C12 2 mg/l Probability: 77.1% [95%CI, %] for weight = 50 kg and 70.6% [95%CI, %] for weight = 58 kg). Sci Rep Nov 23;7(1):16187.

26 Effectiveness of half-a-tablet Efavirenz+2 NRTIs Prospective, single-arm study (April 2013 to August 2017) Inclusion criteria: Pt > 18 y/o with EFV based cart (EFV+2NRTIs) and EFV conc.(c12) > 2 mg/l HIV-1 didn t harbor resistance mutations to EFV or NRTIs Exclusion criteria: Pregnant, or critically ill Receiving anti-tuberculous agents, anti-epilepticus or protease inhibitors Questionable adherence to cart Intervention: The 600 mg EFV tablet was reduced to half a tablet daily with the use of a pill cutter Monitor: PVL, CD4 count before dose reduction and every 12 weeks (for 48 weeks) then every 24 weeks, EFV C12 (2~12 weeks later)

27 Effectiveness of half-a-tablet Efavirenz+2 NRTIs

28 Effectiveness of halt-a-tablet Efavirenz+2 NRTIs

29 Effectiveness of halt-a-tablet Efavirenz+2 NRTIs After halving the dose of EFV, Plasma EFV C12 decreased to 1.59mg/L (IQR,1.23 to 2.03mg/L), with a reduction of 47.4%(IQR, %) from baseline. 92.0% patients continued to maintain EFV C12 1mg/L.

30 Effectiveness of half-a-tablet Efavirenz+2 NRTIs Snapshot analysis of primary and secondary outcomes after switch to combination antiretroviral therapy containing half a tablet efavirenz +2NRTIs

31 Effectiveness of half-a-tablet Efavirenz+2 NRTIs Specific adverse effects before and after switch of regimens containing full dose EFV to half a tablet efavirenz +2NRTIs

32 Nevirapine Presence of tablet remnants of NVP XR in stools was reported in 1.19% and 3.05% of subjects in two clinical trials. Impact on virological outcome? Study: From April to December, 2014, we enrolled HIV-infected patients who switched to NVP XR+2NRTIs. Face to face questionnaire PLoS One Oct 14;10(10):e

33 Comparisons of baseline clinical characteristics of HIV-1-infected patients who noticed and those who did not notice tablet remnants of nevirapine extended-release (NVP-XR) in stools. 22.1%

34 Comparisons in pts who underwent therapeutic drug monitoring of plasma concentration of NVP

35 Comparisons in pts who underwent therapeutic drug monitoring of plasma concentration of NVP The presence of tablet remnants of NVP XR in stools is not uncommon in HIV-1-infected Taiwanese patients receiving NVP XR-based antiretroviral regimens, which does not have an adverse impact on the virological and immunological outcomes.

36 Summary TDM may be helpful in selected patient group treated with cart. Personalized medicine based on integrated genetic profiling and TDM approaches should guide clinicians to make better therapeutic choice, facilitating treatment benefit and toxicity predictions.

37 Case Discussion

38 Case 40y/o male, BH: 173 kg, BW: 78 kg PMH: Syphilis(treated), Eczema Adherence: good HAART 2009: EFV 600 mg+2nrtis CD4: 61, PVL: ADR: heat sensation after EFV 2010/10: EFV C12: 2.55 mg/l CYP2B6 GT genotype 2014/06: reduce to EFV 0.5 tab 2014/07: EFV C12: 1.57 mg/l Concurrent drugs: nil Hepatitis profile HBsAg (-) Anti-HBs (+) Anti-HBc (+) Anti-HCV ab(-) Anti-HAV(+) Lab data Scre: 0.8 mg/dl AST/ALT/Bil: WNL

39 Case_Recent HIV status PVL(cp/mL)) CD4 count

40 What should we do? Perform TDM? Switch to other regimen? Do HIV drug-resistance test?

41 Case_Recent HIV status Check resistance profile Switch back to Atripla He discontinue HAART for several weeks due to newly diagnosis of HCC PVL(cp/mL)) CD4 count

42 Case_Recent HIV status Check resistance profile Switch back to Atripla PVL(cp/mL)) CD4 count

43 Case_Recent HIV status Check resistance profile Switch back to Atripla PVL(cp/mL)) CD4 count

44 Acknowledgement Professor Chien-Ching Hung Sung-Hsi Huang Sue-Yo Tang Kuan-Yeh Lee Wen-Chun Liu Hsin-Yun Sun Chin-Fu Hsiao Ching-Hua Kuo Yi-Ching Su Mao-Song Tsai Pei-Ying Wu Bing-Ru Wu Shang-Ping Yang Assistant professor Shu-Wen Lin Professor Sui-Yuan Chang