PK variability of antiretrovirals in the clinical setting: which lesson for clinicians?

Transcription

1 PK variability of antiretrovirals in the clinical setting: which lesson for clinicians? Dario Cattaneo, PharmD, PhD Unit of Clinical Pharmacology Luigi Sacco University Hospital, Milano, ITALY

2 My disclosures It is impossible to speak of pharmacokinetic (PK) variability without mentioning TDM!!! I will talk of antiretrovirals PK variability using real life data

3 The fact A retrospective analysis of routine TDM of antiretrovirals at the Luigi Sacco University Hospital, Milan, Italy, between January 2010 and May Cattaneo, AIDS

4 The fact - Cattaneo, AIDS

5 The fact ARV Sanples (n) Interindividual CV (%) Nevirapine % Efavirenz % Lopinavir % Elvitegravir % Darunavir % Dolutegravir % Etravirine % Maraviroc % Tenofovir % Atazanavir % Raltegravir % 4-fold difference! these drugs are mostly given at the same doses in all patients 1 Cattaneo, AIDS 2014, 2 Cattaneo In J Pharm 2016, 3 Cattaneo Antiviral Ther 2017

6 How to explain pk variability check for right methodology first!!

7 From the lab

8 From the lab The accuracy of an analytical method describes the closeness of mean test results obtained by the method to the actual concentration)of the analyte. The mean value should be within 15% of the nominal value The precision of an analytical method describes the closeness of individual measures of an analyte when the procedure is applied repeatedly to multiple aliquots of a single homogeneous volume of biological matrix. The precision determined at each concentration level should not exceed 15% of the coefficient of variation Take home message for clinicians Up to 15% of PK variability may be driven by uncertainties in lab measurements

9 to the bedside 420 requests of TDM in a month. Available information: - patient s age: 95% - patient s body weight: 56% - reason fo TDM: 55% - transaminases: 6% - serum creatinine: 53% 37% of the samples were at steady state 19% of the samples were collected at the right time (for 81% of samples nobody knew at what time the blood was drawn ) - Irshaid et al, Clin Lab

10 How to explain pk variability check for right methodology first!! consider the role of HIV per se

11 Altered activity in HIV-pts vs. age and sex-matched healthy volunteers CYP3A4-18% CYP2D6-90% N-acetyltransferase 2-53% Xantine Oxydase +22% Conclusions Infection with HIV or stage of HIV infection may alter Phase I and II drug metabolizing enzyme activity. HIV infection was related to an increase in variability of these drug-metabolizing enzymes. Altered metabolism may be a consequence of immune activation and cytokine exposure. - Jones, Eur J Clin Pharmacol

12 How to explain pk variability check for right methodology first!! consider the role of HIV per se think about other co-morbidities

13 kidney impairment. 1tablet/96h 1tablet/48h 1tablet/24h - Kearney, Clin Pharmacokinet

14 rilpivirine exposure is lower during pregnancy and highly variable - Tran, JAIDS

15 How to explain pk variability check for right methodology first!! consider the role of HIV per se think about other co-morbidities remember DDIs

16 The study included 144 HIV-infected individuals who provided 186 and 167 elvitegravir and cobicistat plasma concentrations, respectively (NONMEM analysis); Clearance was 7.6 L/h (CV 16.6%) for elvitegravir and 16.0 L/h (CV 41.9%) for cobicistat; Concomitant administration of non-ritonavir-boosted atazanavir decreased elvitegravir clearance by 35% (UGT1A1 inhibition) and decreased cobicistat clearance by 47%. - Barcelò, JAC

17 TDF, ng/ml Effect of cobicistat on tenofovir plasma concentration Pis/r NNRTIs RAL * ELV/ COBI Multivariate analysis beta std dev p-value Concomitant ART <.0001 COBICISTAT vs PI INI vs PI NNRTI vs PI SEX (F vs M) Co-infections (NO vs YES) CD4 [0-250] vs [ ] [ ] vs [ >500] Viral load (>=37 vs <37) Days of TDF therapy <=1y vs >6y (1y-3y] vs >6y (3y-6y] vs >6y Age Weight Creatinine <.0001 *p<0.001 vs all other groups - Gervasoni, CROI

18 How to explain pk variability check for right methodology first!! consider the role of HIV per se think about other co-morbidities remember DDIs verify patients compliance

19 [ATV] trough, ng/ml Poor adherence may add great variability to drug Pk Nearly 5% of samples resulted below LOQ (20 ng/ml) - Gervasoni, Plos One

20 How to explain pk variability check for right methodology first!! consider the role of HIV per se think about other co-morbidities remember DDIs verify patients compliance make sure on the correctness of drug intake

21 When (also) the food can make the difference Take STRIBILD with food. Take your pill with food, this helps get the right amount of medicine in your body

22 When (also) the food can make the difference 75 HIV-infected patients treated with Stribild for at least one month, with at least one request TDM, no clinical evidence of GI impairment and not given drugs known to affect ELV or TDF pk 9% 15% 23% breakfast (fed) lunch (fed) supper (fed) 17% mid-morning (fasting) 36% late-evening (fasting) 24% of patients assumed Stribild in fasting conditions - Cattaneo et al, Int J Pharm

23 When (also) the food can make the difference 12 out of the 75 patients (16%) had elvitegravir concentrations below the lower limit of quantification of the assay - Cattaneo et al, Int J Pharm

24 The type of food is likely to play a key role on interindividual PK variability of Stribild - Cattaneo et al, Int J Pharm

25 How to explain pk variability check for right methodology first!! consider the role of HIV per se think about other co-morbidities remember DDIs verify patients compliance make sure on the correctness of drug intake think of genetic background

26 Results: CYP2B6*6 and *18 variant alleles, weight and sex were the most significant covariates explaining 55% of inter-individual variability in EFV clearance

27 More players you have more complex might be the game HIV-infected women (n=101) on tenofovir-based therapy (300 mg qd). The media tenofovir AUCs: 3350 ( ) ng*h/ml - Baxi, AIDS

28 High inter-individual pharmacokinetics as an opportunity?!?

29 [ATV] trough, ng/ml How to read inter-individual pk? First viewpoint as an option to reduce drug dose to limit the development of concentrationrelated toxicity?? - HSacco data -

30 Distribution of ATV plasma trough concentrations according to drug dosage and therapeutic window ATV, ng/ml (mean ± SD) <150 ng/ml ng/ml >800 ng/ml All evaluations (n=240) 766 ± % 44.3% 34.4% ATV/r 300/100 mg qd (60%) 939 ± % 44.5% 43.9% ATV 400 mg* (28%) 490 ± % 44.7% 19.8% *given either as 400 mg qd or 200 mg bid - Gervasoni, Plos One

31 [ATV], ng/ml Box plot of ATV plasma trough concentrations clustered according to hyperbilirubinemia grade * 2000 * * grade hyperbilirubinemia.*p<0.01 vs grade 0 - Gervasoni, Plos One

32 ATV plasma trough concentrations in patients that did or did not experience drug-related adverse events ATV, ng/ml Hyperbilirubinemia 1 (n=125) 1025 ± 920* Dyslipidemia 2 (n=116) 804 ± 824* Kidney stones 3 (n=13) 1121 ± 886* No ATV-related complications (n=71) 461 ± 678 *p<0.001 vs No ATV-related complications NB: ATV-related adverse events more frequent in patients treated with the 300/100 qd regimen. - Gervasoni, Plos One

33 Start with ATV/r 300/100 mg qd Measurement of ATV trough conc. [ATV] ng/ml No changes of drug dose [ATV] <150 ng/ml Check for -Compliance? -Atypical PK? -lab/sampling error? [ATV] >800 ng/ml Consider to move to 200/100 qd or 200 bid - HSacco data -

34 Atazanavir Pk variability can be reduced also trough pharmacogenetics Average atazanavir exposure was 253 ng/ml ( ) in the pg arm versus 111 ng/ml (64 190) in the standard-dose arm (P,0.001); 28 patients in the pharmacogenetic arm (75.7%) had atazanavir conc. >150 ng/ml versus 14 patients (38.9%) in the standard-dose arm (P<0.001). - Bonora, JAC

35 TDF C trough (ng/ml) TDF, ng/ml An approach not always feasible the case of TDF 100 pts on TDF 300 mg/day 300 P= ± ± Inter-CV: 89.1% Intra- CV: 36.0% 0 Tox No Tox Yes - Gervasoni, PLOS One 2014-

36 Tenofovir, ng/ml How to adjust in these cases? <50 kg >50 kg Females - Gervasoni, PLOS One Nishijima, PlosOne

37 [ATV] trough, ng/ml How to read inter-individual pk? Second viewpoint as an option to reduce drug dose to limit the development of concentrationrelated toxicity?? as an option to increase drug dose to limit the risk of failure to treatment?? - HSacco data -

38 The case of darunavir EC 90 for resistant virus (2000 ng/ml) 1000 EC 90 for WT virus (200 ng/ml) 0 DRV/rtv 600/100 bid DRV/rtv 800/100 qd (L.Sacco data )

39 Can variability in the ARVs PK impact on patients outcome? Patients (7/50) which developed de novo and transient NNRTI-related mutations when treatment was interrupted (guided by CD4 cell count and plasma viremia) Presence of NNRTI mutations Pt ID NNRTI Time below cutoff, % CV% A Efavirenz % A Efavirenz % B Efavirenz % D Nevirapine % E nevirapine % Absence of NNRTI mutations B Efavirenz 100 0% C Efavirenz 0 8.3% C Efavirenz % F Nevirapine 0 7.6% F nevirapine 0 9.1% P-value Emergence of resistant variants after interruption was associated with a higher CV% in NNRTI plasma concentrations during treatment period -Darwich, Antiviral Ther

40 -Fabbiani JAC

41 What about intra-patient variability? Intra-individual coefficient of variation (ICV%) was determined in 6 drug for 10 HIV-infected patients ARV ICV (%) Lopinavir 24-51% Nelfinavir M % Ritonavir 34-43% Saquinavir 52-55% Efavirenz 7-29% Nevirapine 25% Overall PIs 43.5% Overall NNRTIs 25% - Nettles, Clin Infec Dis

42 Things may sound better with boosted PIs

43 RAL, ng/ml RAL, ng/ml..but not for raltegravir.. N of pts Intra-individual CV (%) Cattaneo et al, % (18-124%) Siccardi et al, % (64-265%) Fortuna, et al % (65-94%) Pt. 014 (1 day interval) Pt. 006 (1 day interval) Time, min Time, min - Cattaneo, J Antimicrob Chemother

44 When pharmacokinetics can be considered as highly variable?

45 Take-home message Low intraindividual variability in drug concentrations is a mandatory requisite for the application of TDM

46 Which lessons for clinicians? The one-size (dose) fits all approach is associated with great interindividual variability in antiretroviral pharmacokinetics; Different covariates explaining ARVs PK variability have been identified. Their identification is critical for the interpretation of ARV PK; The PK of some ARVs (raltegravir) is characterized also by a wide intra-individual variability. For these drugs, TDM is of limited clinical value; The reduction of ARV PK variability may improve clinical outcome, provided that pharmaceutical formulations are available for a fine adjustment of drug doses

47 Thank you!..people from the lab Simone Stefania Dario Sara Stefy Serena Valeria Roberta and infectivologists... Cristina Gervasoni Amedeo Capetti Valentina di Cristo Simona Landonio Paola Meraviglia Laura Milazzo Davide Minisci Diletta Pezzani Chiara Resnati Agostino Riva Stefano Rusconi Francesco Simonetti Salvatore Sollima Massimo Galli Giuliano Rizzardini