Friday afternoon Programme

Friday afternoon Programme Pharmacology and TDM Dr Marta Boffito Consultant Physician, C&W Resistance to new anti-retrovirals Dr Steve Taylor Consultant Physician, Birmingham HIVPA Annual Conference 2008 Jurys Hotel, Bristol 1

Phones on silent please Pharmacology & TDM Dr Marta Boffito Chelsea & Westminster Hospital 2

Miss X Ex- IVDU HIV+ since 1996 Several treatments in the past, including dual NRTI therapy Intolerant to low dose RTV Refuses T-20 CD4 160 VL 70,000 Currently off therapy What tests? 1. Repeat CD4 count and viral load 2. Urine drug screen and HIV tropism 3. Resistance test 4. Resistant test and HIV tropism 5. None 3

Resistance Test NRTI / NtRTI mutations 41L, 67G, 70R, 210W, 215Y 74V 184V 44D +118I 69A NNRTI mutations 103N, 106I PI mutations Major: I50V, L90M Minor: L10V, L33F Other: I13V, K20R, M36I, L89I http://hivdb.stanford.edu N-Nt RTI 3TC Resistance ABC Resistance AZT Resistance D4T Resistance DDI Resistance FTC Resistance TDF Intermediate resistance NNRTI EFV High-level resistance ETV Potential low-level resistance NVP High-level resistance 4

http://hivdb.stanford.edu Protease Inhibitors ATV Low-level resistance DRV Intermediate resistance FPV High-level resistance IDV Low-level resistance LPV Intermediate resistance NFV Intermediate resistance SQV Intermediate resistance TPV Potential low-level resistance What drug classes? 1. NRTI + boosted PI 2. NRTI + NNRTI 3. NNRTI + PI/r + integrase inhibitor 4. NNRTI + PI* + integrase inhibitor + CCR5-ant 5. PI* + integrase inhibitor + CCR5-ant *unboosted 5

Active/available agents Tenofovir? TDF/FTC? Etravirine 200 mg BID Raltegravir 400 mg BID Atazanavir 400 or 300/100 mg OD? Maraviroc what dose? What drugs (previous slide) cannot be co-administered? 1. FTC and raltegravir 2. Etravirine and atazanavir 3. Etravirine and maraviroc 4. Etravirine and raltegravir 5. Tenofovir and atazanavir/ritonavir 6

Effect of PIs on ETV 80% TMC125 Cmin increased by 58 and 25% 60% 50% 51% Change in ETV AUC 40% 20% 0% -20% -40% -60% -80% TPV/r -76% Full-dose RTV -46% DRV/r -37% 17% 30% LPV/r ATV/r ATV IDV Comparable to historic control FPV/r No dose adjustment necessary Dose adjustment or alternative may be necessary Contraindicated Kakuda et al. 2006 Effect of ETV on PIs 80% 60% ATV Cmin decreased by 47 and 38% 69% Change in PI AUC 40% 20% 0% -20% -40% -60% -80% SQV SQV IDV LPV/r LPV/r ATV ATV/r -52% -46% -13% -18% -20% -17% -14% 6% 18% DRV/r TPV/r FPV/r No dose adjustment necessary Dose adjustment or alternative may be necessary Contraindicated Kakuda et al. 2006 7

ATV + TDF When ATV 400 mg + TFV co-administered ATV C min decreases by 28-40% When co-dosed with TDF, ATV should be combined with RTV The decrease in ATV C min is 25% ATV dose increase in experienced pts has been taken into consideration t1 PK evaluation of ETV and raltegravir in healthy volunteers 1,000 10,000 ETV (ng/ml) 100 0 ETV + RAL ETV alone 2 4 6 8 10 12 Time (hours) RAL (ng/ml) 1,000 100 0 ETV + RAL RAL alone 2 4 6 8 10 12 Time (hours) Anderson et al. 2007 8

Slide 16 t1 Although the researchers figured that a 34% lower raltegravir trough with etravirine than without it should not necessitate a dose adjustment, the 90% confidence interval around that trough (0.34 to 1.26) indicates wide trough variability from person to person, not an unusual finding in these kinds of studies. Still, the reported variability means raltegravir troughs fell up to two thirds lower with etravirine than without it in a few people, and for those few people one would have less confidence saying the change lacks clinical meaning. temp, 03/12/2007

Raltegravir + ATV RAL % change 100 90 80 70 60 50 40 30 20 10 0 C 12 AUC C max ATV/r ATV unboosted Isentress Prescribing Information Miss X TVD 1 tablet OD ETV 200 mg BID RAL 400 mg BID ATV/r 300/100 mg OD PLAN: when VL< 50 and tropism available, REPLACE ATV/r WITH MRV 9

Other drugs 2 days before re-starting you receive a letter from her GP saying that the methadone dose has been reduced to 50 mg daily What do you do now? 1. Prescribe only NRTIs 2. Avoid NNRTIs 3. Consult HIV-druginteractions.org 4. Write to GP to increase methadone dose 5. Refer the patient to Dr Pozniak 10

Etravirine and methadone No dose adjustments required Clinical monitoring for withdrawal symptoms is recommended Co-administration - increased: C max, AUC, C min of R-methadone by 2-10% - decreased: C max, AUC, C min of S-methadone by 11% 11

Maraviroc drug interaction summary Interacting Drug Saquinavir/r Atazanavir/r Lopinavir/r Tipranavir/r Ritonavir LPV/r + efavirenz Efavirenz Nevirapine Tenofovir Rifampicin Effect of other ARV on MRV AUC 10-fold 4.9-fold 4.0-fold 2.0-fold 2.5-fold 50% 70% Abel et al. 2005 t2 Maraviroc + etravirine Effect of ETV on MRV PKs C max AUC -50-51 -52-53 -54-55 -56-57 -58-59 -60-61 -62-63 -64-65 Data consistent with ETV acting as a potent inducer of MRV metabolism In the absence of potent CYP3A4 inhibitors such as RTV, the recommended clinical dose for MRV is 600 mg BID Davis et al. 2007 12

Slide 24 t2 Co-administration of etravirine with maraviroc decreased the exposure of maraviroc by 53% and 60% for AUC12 and Cmax respectively compared to maraviroc alone. These data are consistent with etravirine acting as a potent inducer of the metabolism of maraviroc. As such, in the absence of potent CYP3A4 inhibitors such as protease inhibitors, the recommended clinical dose for maraviroc is 600 mg bid. temp, 26/11/2007

t3 Maraviroc + etravirine + darunavir/ritonavir Effect of ETV + DRV/r on MRV PKs 250 200 150 100 50 0 C max AUC Net increase in MRV concentrations consistent with previous inducer/inhibitor combination data: effect appears to be inhibition Recommended clinical dose for MRV in the presence of boosted PIs is 150 mg BID What dose of maraviroc? 1. 100 mg BID 2. 300 mg BID 3. 600 mg OD 4. 150 mg BID 5. 600 mg BID 13

Slide 25 t3 Co-administration of etravirine/darunavir/ritonavir with maraviroc increased the exposure of maraviroc by 210% and 77% for AUC12 and Cmax respectively compared to maraviroc alone. These results, where the combination of a potent inducer of CYP mediated metabolism (etravirine) and a potent inhibitor of CYP mediated metabolism (darunavir / ritonavir) yields a net increase in maraviroc concentrations, are consistent with previous inducer/inhibitor combination data, where the net effect appears to be inhibition. As such, the recommended clinical dose for maraviroc in the presence of boosted PIs (including etravirine/darunavir/ritonavir) should be 150mg bid. TMC125 pharmacokinetic data showed no effect of maraviroc on TMC125 pharmacokinetics. Therefore, no dose adjustment of TMC125 is necessary. The dose remains 200 mg b.i.d.. temp, 26/11/2007

Summary of dose modifications with maraviroc Concomitant treatment Includes a potent CYP3A4 inhibitor For example: Protease inhibitors* ± ritonavir (except tipranavir) Elvitegravir, delavirdine Ketoconazole, itraconazole, clarithromycin, telithromycin, nefazadone, telithromycin YES Regardless of other agents in the regimen Morning dose 150 mg Evening dose 150 mg NO Includes a CYP3A4 inducer For example: Efavirenz, etravirine Rifampicin NO NO CYP3A4 inhibitors or inducers For example: NRTIs, also nevirapine, tipranavir/r YES 300 mg 300 mg 300 mg 300 mg 300 mg 300 mg *including darunavir Davis et al. 2007 www.hiv-druginteractions.org 14

E. C. Male, HIV+ since 2004 CD4 211 (17%) cells/mm 3 VL 29,000 copies/ml History of epilepsy Stable on carbamazepine (Ca) and phenytoin (Ph) 15

E. C. Ca and Ph are inducers of different CYP450 enzymes (CYP3A4) Metabolized by CYP3A4 Interaction between Ca and EFV documented EFV and carbamazepine Arm Drug PK parameter GMR and 90% CI EFV + CBZ vs. EFV CBZ + EFV vs. CBZ A* EFV C max AUC C min 0.792 (0.740-0.848) 0.637 (0.601-0.676) 0.526 (0.470-0.490) B** CBZ C max AUC C min 0.804 (0.761-0.849) 0.729 (0.668-0.796) 0.652 (0.560-0.760) CBZE^ C max AUC C min 01.050 (0.905-1.219) 0.989 (0.854-1.145) 0.866 (0.703-1.066) ^CBZE = carbamazepine epoxide *n=18, EFV 600 mg OD days 1-14, EFV 600 mg OD days 15-35 plus carb 200 first then 400 mg OD up to day 35 **n=18, carb 200 first then 400 mg OD up to day 21, carb 400 mg OD plus EFV 600 mg days 22-35 Kaul et al. 2006 16

E. C. Ca and Ph are inducers of different CYP450 enzymes (CYP3A4) Metabolized by CYP3A4 Interaction between Ca and EFV documented Interaction between Ph and LPV/r documented Phenytoin and LPV/r 14 12 10 LPV/r alone LPV/r + phenytoin 16 14 12 Phenytoin alone Phenytoin + LPV/r [Lopinavir] µg/m 8 6 4 [Phenytoin] µg/m 10 8 6 4 2 2 0 0 2 4 6 8 10 12 0 0 2 4 6 12 24 Time (h) Time (h) Phenytoin was also found to reduce the concentration of RTV Lim et al. 2004 17

What are the options for E. C.? 1) Stop Ca and Ph and prescribe alternative antiepileptic (i.e. levetiracetam) 2) Valproate and lamotrigine might be safe with NNRTI (more data needed) 3) Initiate a 4 NRTI regimen for HIV (i.e. AZT/3TC/ABC/TDF) 4) Other? R. E. Male, HIV+ 1 month ago CD4 101 (15%) cells/mm 3 VL 89,000 copies/ml Primary transmitted resistance (103N) Recreational drugs: ectasy (MDMA) 18

R. E. MDMA metabolized CYP2D6, CYP1A2, CYP2B6, CYP3A4 RTV inhibits CYP3A4 & CYP2D6 Caution when prescribing PI/r Systemic circulation heart rate BP Tremor Sweating Bruxism Hyperthermia Rhabdomyolysis Intravasc. coagulation Acute Renal failure Ecstasy CYP2D6 CYP3A4 RTV Portal vein 19

G. B. 55 year old HIV+ (since 1998) male On TDF/FTC/LPV/r CD4 210 cells/mm 3 ; VL < 50 copies/ml History of depression currently untreated Admitted to A&E complaining of vomiting, extreme weakness, palpitations, confusion Few days later comes to HIV clinic for regular follow up and reports recent anxiety attacks My GP gave me this G. B. Propranolol 40 mg RTV CYP2D6 COMMUNICATION BETWEEN HIV SPECIALISTS AND GP 20

Patient Case HIV+ (1994) 32 y.o. Cx M 2/2001-10/2003 d4t + 3TC + NVP VL 50,000 RT: 75I, 98S, 181C, 184V, 221Y 10/2003 5/2005 TDF + ddi + LPV/r TDF + FTC + ATV/r (1) Patient happy with his OD regimen Complains of heartburn Ranitidine 150 mg BD prescribed (2) (2) (1) (3) In ATV/r Would H.V, + ATV FAM you AUC 40 switch mg and BDC min in the H.V: by PI ATV 25% to AUC, and one 26% that C max compared, does C min not 18%, to ATV/r interact 14%, 300/100 28% with mg HIV Efficacy H 2 blocker patients-intragastric of ATV/r and + TDF? in ph treatmentexperienced patients demonstrated in higher? in ATV may study 045 1 be avoided by temporal separation of ATV/r and FAM-BD? TDM: ATV C trough : 98 (MEC = 150 ng/ml) (3) CD4 528 VL<50 5/2005 7/2006 8/2006 Time (month) 1.Johnson M, et al. AIDS 2005;19:685 694 Patient Case HIV+ (1994) 38 y.o. Cx M CD4 189, VL 130,000 Wild type (1) (2) (3) In ATV/r Inter H.V, + individual ATV FAM AUC 40 mg and BD variability C min in H.V: by ATV 25% in and AUC, 26% C max compared, C min 18%, to ATV/r 14%, 300/100 28% mg drug levels and interaction Efficacy HIV outcomes patients-intragastric of ATV/r + TDF in ph treatmentexperienced patients demonstrated in higher? in ATV may be avoided by temporal study 045 separation of ATV/r and FAM-BD? TDF + FTC + ATV/r (1) Patient happy with his OD regimen, Sees his GP because of heartburn GP prescribes ranitidine 150 mg BD (2) ATV C trough : 405 (MEC = 150 ng/ml) (3) CD4 333 VL<50 12/2004 9/2006 Time (month) 10/2006 1.Johnson M, et al. AIDS 2005;19:685 694 21