8. PHARMACOKINETICS OF ANTIRETROVIRAL AND ANTI-HCV AGENTS David Burger José Moltó Table 8.1a: INFLUENCE OF FOOD ON ABSORPTION (AREA UNDER THE CURVE) OF ANTIRETROVIRAL AGENTS NUCLEOSIDE ANALOGUES NtRTI Fasting Low-fat meal High-fat meal Recommendation Zidovudine + + + None Didanosine + - - Fasting Stavudine + + + None Lamivudine + + + None Abacavir + + + None Emtricitabine + + + None Tenofovir + + + None Saquinavir - - + High-fat meal Ritonavir - + + Meal PROTEASE INHIBITORS Saquinavir (+ Ritonavir) - + + High-fat meal Indinavir + + - Fasting Indinavir (+ Ritonavir) + + + None* Fosamprenavir + + + None Lopinavir - + + Meal Atazanavir - + + Meal Tipranavir - + + Meal Darunavir - + + Meal 491
NNRTIs Fasting Low-fat meal High-fat meal Recommendation Nevirapine + + + None Delavirdine + - - Fasting Efavirenz + + + None Etravirine - + + Meal Rilpivirine - + + Meal Raltegravir + + + None INTEGRASE INHIBITORS Elvitegravir - + - Meal Dolutegravir + + + None** CCR5 ANTAGONISTS Maraviroc + + + None * Intake with food is advised because this reduces indinavir peak concentrations without influencing the AUC, this may reduce the incidence of nephrolithiasis ** Intake of dolutegravir with food is recommended in case of treatment of patients with integrase resistance 492
Table 8.1b: INFLUENCE OF FOOD ON ABSORPTION (AREA UNDER THE CURVE) OF ANTI-HCV AGENTS Fasting Low-fat meal High-fat meal Recommendation Ribavirin - + + Meal Sofosbuvir - + + Meal Simeprevir - + + Meal Daclatasvir + + + None Sofosbuvir+ Ledipasvir Sofosbuvir + Velpatasvir Paritaprevir+ Ritonavir+ Ombitasvir + + + None + + + None - + + Meal Dasabuvir + + + None Grazoprevir+ Elbasvir + + + None 493
Table 8.2a: PHARMACOKINETIC PARAMETERS OF ANTIRETROVIRAL AGENTS NUCLEOSIDE ANALOGUES F Tmax T-half Vd (L/kg) CL/F (L/hr.kg) Fu Fe Zidovudine 65 1 1 1.4 30 75 20 Didanosine 40 1 1.5 0.8 12 >95 50 Stavudine 85 1 1 1 8 >95 50 Lamivudine 80 1 6 1.3 7 >95 70 Abacavir 83 1.5 1.5 0.7 1.5 50 <2 Emtricitabine 93 2 8 0.26 >96 86 NtRTI PROTEASE INHIBITORS NNRTIs Tenofovir DF 35 1-2 15 0.8 0.23 <0.7 70-80 Tenofovir AF 1 23 <0.7 70-80 Saquinavir 4 2-3 7-12 10 0.7-1.4 < 2 < 5 Ritonavir 70 2-4 3-5 0.4 0.1-0.2 < 2 < 5 Indinavir 60 1 2 0.4 0.7 40 10-20 Nelfinavir 80 2-4 3-5 2-7 0.7 < 2 < 5 Lopinavir 4 5-6 0.7 0.1 <2 2 Atazanavir 2.5 6.5-8 1.6-2.7 0.4 14 7 Fosamprenavir 2.5 7.7 6 0.6 10 <1 Tipranavir 2 6 0.02 <1 <1 Darunavir 82 2.5-4 15 1.9 0.1 5 8 Nevirapine 93 5 30 1.4 0.04 40 <5 Delavirdine 70 2 6 0.7 0.1 <2 <5 Efavirenz 66 66 40-55 2.4 0.7 <1 <1 Etravirine 3 41 <1 <1 Rilpivirine 4 45 10 <1 <1 494
F Tmax T-half Vd (L/kg) CL/F (L/hr.kg) Fu Fe Raltegravir 3 9 17 9 INTEGRASE INHIBITORS Elvitegravir/c 4 12.9 1-2 6.7 Dolutegravir 2-3 14 0.25 0.014 <1 <1 ENTRY INHIBITORS Maraviroc 33 2 13.2 2.8 1.9 24 8 Enfuvirtide 84 4 3.8 0.08 0.03 8 F: oral bioavailabiltiy; Tmax: time to maximum concentration; T-half: elimination halflife; Vd/F: apparent volume of distribution; CL/F: apparent oral clearance; Fu: fraction unbound to protein; Fe: fraction of the dose excreted unchanged in urine. 495
Table 8. 2b: PHARMACOKINETIC PARAMETERS OF ANTI-HCV AGENTS F Tmax T-half Vd (L/kg) CL/F (L/ hr.kg) Fu Ribavirin 45-65 2 300 40-71 0.5 100 17 Sofosbuvir 0.5-2 0.4 35-39 Simeprevir 4-6 41 <1 <1 Daclatasvir 1-2 12-15 0.67 0.06 1 6.6 Ledipasvir 4 47 1 Fe Velpatasvir 3 15 <0.5 <0.4 Paritaprevir 4-5 5.5 1-3 Ombitasvir 4-5 21-25 Dasabuvir 4-5 0.1 Grazoprevir 2 31 17.9 <1.2 <1 Elbasvir 3 24 9.7 <0.1 <1 F: oral bioavailabiltiy; Tmax: time to maximum concentration; T-half: elimination halflife; Vd/F: apparent volume of distribution; CL/F: apparent oral clearance; Fu: fraction unbound to protein; Fe: fraction of the dose excreted unchanged in urine. 496
Table 8. 3a: PLASMA DRUG CONCENTRATIONS OF ANTIRETROVIRAL AGENTS NUCLEOSIDE ANALOGUES Dose (mg) Dose interval Cmax (mg/l) Cmin (mg/l) AUC (mg/l.hr) Zidovudine 300mg 12 1.8 < 0.02 1.7 Didanosine 200mg 12 0.8 < 0.01 1.20 Didanosine 24 1.6 < 0.01 2.36 Stavudine 40mg 12 0.7-2.0 0.02 1.3 Lamivudine 150mg 12 0.6 0.1 2.4 Abacavir 300mg 12 3 < 0.1 6.2 Emtricitabine 200mg 24 1.7 0.05 8.0 NtRTI Tenofovir DF 245mg 24 0.3 < 0.1 2-3 Tenofovir AF 25mg 24 0.015 0.010 0.25 Saquinavir (Fortovase) 1200mg 8 2.2 0.2 7.2 PROTEASE INHIBITORS Saquinavir (Invirase) 1200mg 8 0.72 0.08 2.3 Ritonavir 600mg 12 14 1 70 Indinavir 800mg 8 8 0.15 19 Fosamprenavir 1 12 4.8 0.35 33 Lopinavir* 12 9.6 5.5 83 Atazanavir 24 3-5 0.2 20 Tipranavir* 500 12 46 21 425 Darunavir* 600 12 6.4 3.5 62 497
NNRTIs Nevirapine Dose (mg) Dose interval Cmax (mg/l) Cmin (mg/l) AUC (mg/l.hr) 200mg 12 5.9 3.9 55 24 6.7 2.9 106 Delavirdine 8 16 3-8 80 Efavirenz 600mg 24 4 1.8 58 Etravirine 200mg 12 0.45 0.2 4.5 Rilpivirine 25mg 24 0.26 0.10 3.6 Raltegravir 12 5.0 0.06 6.3 INTEGRASE INHIBITORS Elvitegravir/c 150mg 24 1.7 0.45 23 Dolutegravir 50mg 24 3.7 1.1 53 ENTRY INHIBITORS Enfuvirtide 90mg 12 5.0 3.3 48 Maraviroc 300mg 12 0.6-0.9 0.03-0.04 2.5-3.0 Cmax: maximum plasma concentration (= peak); Cmin: minimum plasma concentration (= trough); AUC: area under the plasma concentration-time curve. * only data available for ritonavir-boosted regimen 498
Table 8. 3b: PLASMA DRUG CONCENTRATIONS OF ANTI-HCV AGENTS Dose (mg) Dose interval Cmax (mg/l) Cmin (mg/l) AUC (mg/l.hr) Ribavirin 800-1000 12 3.6 2.2 25 Sofosbuvir 400 24 0.8-1.0 Simeprevir 150 24 1.9 57 Daclatasvir 60 24 1.5 0.23 14.1 Ledipasvir 100 24 0.32 7.3 Velpatasvir 100 24 0.26 2.97 Paritaprevir 25 24 1.5 7.0 Ombitasvir 150 24 0.13 1.4 Dasabuvir 250 12 1.0 6.8 Grazoprevir 100 24 0.17 0.02 1.4 Elbasvir 50 24 0.12 0.05 1.9 Cmax: maximum plasma concentration (= peak); Cmin: minimum plasma concentration (= trough); AUC: area under the plasma concentration-time curve. * only data available for ritonavir-boosted regimen 499
Table 8. 4: PHARMACOKINETIC PARAMETERS OF HIV PROTEASE INHIBITORS WHEN TAKEN IN DUAL PI OR LOW-DOSE RITONAVIR BOOSTED REGIMENS Saquinavir Saquinavir Dose 1000mg Other PI + dose RTV RTV 100mg Saquinavir 1600mg RTV 100mg Ritonavir Indinavir Ritonavir Indinavir Indinavir Indinavir 800mg 800mg SQV RTV IDV RTV 100mg RTV 200mg RTV 100mg Fosamprenavir 700mg RTV 100mg Fosamprenavir 1 RTV 200mg Atazanavir 300mg RTV 100mg Cmax (mg/l) Cmin (mg/l) AUC (mg/l.hr) 2.5 0.48 16 2.8 0.4 19 6.4 0.4 66 9.2 1.6 55 3.5 0.40 11 8.4 1.6 63 8.3 1.2 46 13.2 3.2 96 4.1 0.17 18 6.1 2.1 40 7.2 1.5 69 4.4 0.7 46 Cmax: maximum plasma concentration (= peak); Cmin: minimum plasma concentration (= trough); AUC: area under the plasma concentration-time curve (for a given dose interval). 500
Table 8. 5a: DOSE ADJUSTMENTS OF ANTIRETROVIRAL AGENTS FOR HEPATIC OR RENAL DYSFUNCTION NUCLEOSIDE ANALOGUES NtRTI PROTEASE INHIBITORS Zidovudine Normal dose 300mg Hepatic dysfunction 3 50-90 Renal dysfunction 10-50 < 10 removed by dialysis 300mg Normal Normal 300mg Yes Didanosine 1 Normal Normal 200mg 100mg Yes Stavudine 40mg Normal Normal 20mg 20mg Yes Lamivudine Abacavir Emtricitabine Tenofovir DF 150mg 300mg 200mg 245mg Normal Normal 100-150mg 25mg Yes 200mg Normal Normal Normal Yes Normal Normal 200mg q2-3 days Normal Normal 245mg q2-4days Tenofovir AF 25mg Normal Normal Normal Saquinavir 1200mg TID 200mg q4 days 245mg q7days Contraindication Yes Yes Yes Normal Normal Normal Normal No Ritonavir 600mg Normal Normal Normal Normal No Indinavir 2 800mg TID 600mg TID Normal Normal Normal Yes Nelfinavir Lopinavir Fosamprenavir Atazanavir Tipranavir 1250mg 1 500mg Normal Normal Normal Normal No - Normal Normal Normal No See 4 Normal Normal Normal No 300mg Normal Normal Normal No Normal Normal Normal Normal No Darunavir 600mg Normal Normal Normal Normal No 501
NNRTIs INTEGRASE INHIBITORS Nevirapine Delavirdine Efavirenz Etravirine Rilpivirine Raltegravir Normal dose TID 600mg 200mg BD 25mg BD Hepatic dysfunction 3 50-90 Elvitegravir/c 125mg Normal Normal Renal dysfunction 10-50 < 10 removed by dialysis Normal Normal Normal Normal Yes Normal Normal Normal Normal No Normal Normal Normal Normal No Normal Normal Normal Normal No Normal Normal Normal Normal No Normal Normal Normal Normal No Not possible Not possible Not possible Dolutegravir 50mg Normal Normal Normal 5 Normal 5 No ENTRY INHIBITORS Enfuvirtide Maraviroc 90mg 300mg BD Normal Normal Normal Unknown No Unknown See 6 See 6 See 6 Yes? 1 Didanosine chewable tablet formulation contains cations (Na, Mg) that can accumulate in patients with significant renal impairment 2 Renal excretion of indinavir increases up to 50% when combined with ritonavir ; consider empirical dosage reduction under the guidance of therapeutic drug monitoring 3 There is not much experience with dosing of antiretroviral agents in hepatic dysfunction; caution is needed; the recommendations are based on patients with mild to moderate hepatic dysfunction; patients with severe hepatic dysfunction should be treated case by case 4 Dosing of fosamprenavir is dependent on Child-Pugh score: 5-6: fosamprenavir 700mg BD + ritonavir 100mg ; 7-9: fosamprenavir 450mg BD + ritonavir 100mg ; 10-15: fosamprenavir 300mg BD + ritonavir 100mg 5 Dolutegravir AUC was decreased by 40% in patients with creatinine clearance <30 ; this is not a concern in patients without integrase resistance but might result in loss of therapeutic effect in patients with integrase resistance. 6 If creatinine clearance: < 80 ml/min: when maraviroc is administered with tipranavir/r: no dose adjustment required. When maraviroc is administered with fosamprenavir/rtv: 150mg. If it is administered with lopinavir/rtv, darunavir/rtv, saquinavir/rtv or atazanavir/rtv: 150mg 502
Table 8. 5b: DOSE ADJUSTMENTS OF ANTI-HCV AGENTS FOR HEPATIC OR RENAL DYSFUNCTION Normal dose Hepatic dysfunction 3 50-90 Ribavirin 1 800-1200 Normal 400-1200mg/ day Renal dysfunction 10-50 200 / on alternate days < 10 200mg Sofosbuvir 400 Normal Normal Normal Contraindicated 3 removed by dialysis Simeprevir 150 Normal 2 Normal Normal Normal No No Yes Daclatasvir 60 Normal Normal Normal Normal No Ledipasvir 100 Normal Normal Normal Normal No Velpatasvir 100 Normal Normal Normal Normal No Paritaprevir 50 Normal 2 Normal Normal Normal Unknown Ombitasvir 150 Normal 2 Normal Normal Normal Unknown Dasabuvir 250 Normal 2 Normal Normal Normal Unknown Grazoprevir 100 Normal 2 Normal Normal Normal No Elbasvir 50 Normal 2 Normal Normal Normal No 1 TDM of ribavirin is recommended 3 SOF is contra-indicated in patients with CrCL < 30 ; if given to these patients the normal dose should be administered PEDIATRIC DOSES OF ANTIRETROVIRAL AGENTS see: http://www.penta-id.org/attachment/up/a2014/files/penta_rx_2014_final_full.pdf 503
THERAPEUTIC DRUG MONITORING (TDM) FOR ANTIRETROVIRAL AGENTS: STATUS AND PERSPECTIVES Current highly active antiretroviral therapies (HAART) result in a significant suppression of HIV replication and in a marked improvement in clinical outcomes. However, the efficacy of antiretroviral treatment may be impaired by several factors, including poor adherence on the part of the patients, the presence of treatment related side effects, selection of antiretroviral-resistant HIV viral strains, and suboptimal concentrations of antiretroviral agents. A growing interest has been generated in recent years regarding the importance of concentrations of antiretroviral agents in plasma, and the role that inadequate drug concentrations may play in treatment failure or drug resistance. Rationale for the Use of TDM of Antiretroviral Therapy Dose-response relationship in which higher doses of the drug are related to a more durable viral suppression exists for many antiretroviral agents. 1-14 Failure to maintain adequate concentrations will eventually allow the development of viral resistance, thereby decreasing the probability of response of current and subsequent therapies. On the other hand, excessively high drug concentrations may contribute, at least in part, to the appearance of antiretroviral therapy-related adverse events. However, the current practice of administering a fixed dosage of antiretroviral agents for all patients produces different concentrations of drugs (interindividual variability). 15-17 Therapeutic drug monitoring (TDM) consists of individualizing dosages with the aim to maintain drug concentrations within a preestablished therapeutic range. The usefulness of this approach to maximize the efficacy while minimizing toxicity of several drugs has been proved in different therapeutic areas, such as antiarrhytmics, anticonvulsants or aminoglycoside antibiotics. Likewise, since HIV suppression seems to be so dependent on adequate drug concentrations, the use of TDM in this scenario would be highly desirable. However, the wide therapeutic range of the new antiretrovirals in current use together with the lack of large-scale prospective studies showing that TDM is a useful tool to improve the management of all HIV-infected subjects who start to take an ARV regimen constitute the main limiting factors for performing TDM in the HIV field. Current Status and Perspectives 18 1. Consider TDM for specific indications patients with significan drug-drug or drug-food interactions patients with changes in pathophysiological state that may impair gastrointestinal, hepatic or renal function 504
in treatment-experienced patients who may have viral isolates with reduced susceptibility to HAART use of alternative dosing regimens whose safety and efficacy have not been established in clinical trials concentration dependent toxicities lack of expected virological response in a treatment naïve person monitoring adherence pregnant or pediatric patients 2. Provide a plasma sample for TDM with at least the following information: patient identifiers indication for TDM dose and frequency of the drug time of last intake of medication and time sample was taken co-medications 3. Take a blood sample noting the correct time after drug intake This requires the patient to have reached the steady state, usually 2 weeks after starting the drug. 4. Use trough samples to monitor virological efficacy and peak samples for toxicity management. Trough samples need to be measured 8h for TID, 12 hours for, and 24 hours for a drug. 5. Undertake TDM for those drugs where a concentration range has been defined (Table 1) 6. Send samples for TDM to a laboratory that you know participates in both internal and external QC programme 7. Monitoring drug concentrations of nucleoside reverse transcriptase inhibitors (NRTIs) NRTIs are metabolized intracellularly and therefore plasma concentrations may not correlate with levels of active intracellular triphosphate which determined the efficacy of the drug. Monitoring plasma concentrations of NRTIs might be useful for the evaluation and management of a drug-drug interaction that affected the plasma concentrations of the NRTI. 8. Make sure that the active metabolite of the drug you are monitoring is being measured, where appropriate. Some drugs have a metabolite component that is measurable and affects the activity of the drug. At present, nelfinavir is the only PI that has a measurable and active metabolite (M8). 9. Only perform TDM as a part of integrated approach in your overall clinical management. TDM can be an extremely valuable tool assisting you in your clinical management of patients, but it is only helpful when combined with other equally important treatment considerations. 10. When performing TDM, take into consideration the intrapatient variability observed with drug concentrations. 505
REFERENCES Activity for an HIV drug across the population may be extremely variable and drug concentration within the therapeutic range does not itsef guarantee a therapeutic concentration at any given time. Levels of systemic exposure to PIs and NNRTIs correlate with their efficacy and some of their adverse effects. Therefore, adjusting PIs and NNRTIs concentrations within a therapeutic window may be of benefit. TDM has potential for patients who are beginning therapy with any PI or NNRTI or who are changing regimens, regardless of treatment history or pharmacoenhancement with ritonavir, to ensure appropriate drug concentrations and to exclude absorption or metabolic problems and unexpected drug-drug interactions 1. Back D, et al. AIDS 2002;S5-S37. 2. Murphy R. AIDS Rev 1999;1:205-212. 3. Drusano GL, et al. J Infect Dis 1998;78:360-367. 4. Reijers MH, et al. AIDS 2000;14:59-67. 5. Burger DM, et al. Antivir Ther 1998;3:215-220. 6. Dieleman JP, et al. AIDS 1999;13:473-478. 7. Gieschke R, et al. Clin Pharmacokinet 1999;37:75-86. 8. Burger D, et al. Ther Monit 2003;25:73-80. 9. Sadler BM, et al. Antimicrob Agents Chemother 2001;45:30-37. 10. Masquelier B, et al. Antimicrob Agents Chemother 2002;46:2926-2932. 11. Marzolini C, et al. AIDS 2001;15:71-75. 12. Veldkamp AL, et al. AIDS 2001;15:1089-1095. 13. Havlir D, et al. J Infect Dis 1995;171:537-545. 14. Gonzalez de Requena D, et al. 12th CROI. Boston, 2005. [abstract 645] 15. Torti C, et al. AIDS Patient Care and STDs 2004;18:629-634. 16. de Maat MM, et al. Ther Monit 2003;25:367-373. 17. Moltó J, et al. Br J Clin Pharmacol 2006;62:560-566. 18. la Porte C, et al. Reviews in Antiviral Therapy 2006; 3: 4-14. 506