Pharmacology Update Alice Tseng, Pharm.D., FCSHP Vancouver May 11, 2005

Transcription

1 Pharmacology Update 2005 Alice Tseng, Pharm.D., FCSHP Vancouver May 11, 2005

2 I m having a Maalox moment!!!

3 Gastric Hypoacidity in HIV 20% incidence in HIV (unrelated to CD 4 ) Antacids, ddi tablets, H2-blockers or proton pump inhibitors (PPI) also affect gastric ph Can lead to drug malabsorption: Atazanavir solubility as ph Also indinavir, delavirdine, keto/itraconazole

4 Use of Gastric Modifying Agents with HAART (n=200) 80% 77% Duration of PPI Use (n=107) 70% 7% 60% 50% 51% 57% 5% 40% 30% 20% 10% 39% 30% 37% 23% 14% 32% 88% 0% Since Starting HAART Within Last Year Within Last Month >8 Weeks 5-8 Weeks <5 Weeks PPI (Rx) PPI/H2 (OTC) Antacid [Luber et al. 7th ICDTH 04, #206]

5 How Gastric Modifiers Affect Antiretroviral Absorption ddi tablets, antacids: Temporarily gastric ph Dose ARVs 1 hour before/2 hrs after antacids H2 blockers, PPI: Steadily blocks secretion of gastric acid May need to alter gastric ph via acidic beverage Using ritonavir as a booster may/may not help

6 Atazanavir Exposure Is Significantly Reduced by Omeprazole % ATV vs. ATV 300/rtv 100 mg QD Omeprazole 40 mg QD in Healthy Subjects (n=48) ATV 300/r OMP ATV 300/r OMP+Cola Cmax AUC Cmin ATV 400/r OMP Atazanavir exposure 70-80% with PPI Effect not corrected with cola or rtv boost In this study, OMP was given 2 hours prior to ATV/r Ongoing study of ATV+ OMP 20 mg [Agarwala et al. CROI 2005, #658]

7 Atazanavir Exposure Is Reduced ~40% by Famotidine % ATV vs. ATV 400 mg QD 100 Atazanavir 400mg + Famotidine 40 mg BID in Healthy Subjects (n=60) Cmax AUC Cmin ATV + FAM ATV + FAM + Cola ATV pm + FAM ATV/r + FAM % ATV vs. ATV 300/100 mg rtv QD Boosted Atazanavir + Famotidine 40 mg BID in Healthy Subjects (n=48): Cmax AUC Cmin ATV/r + FAM ATV/r + FAM + ATV/r 400/100 Cola + FAM [Agarwala et al. 6th IWCPH 2005, #11]

8 Clinical Implications of Coadministering Atazanavir and Gastric Modifying Agents HIV+ Subjects: Mean ATV Cmin (ug/ml) suboptimal ATV Cmin (<0.27 ug/ml) # on ATV/r ATV + H2 (n=20) (20%) 2/4 ATV + PPI (n=15) (40%) 5/6 *Reference Cmin: ATV 400 mg QD: ug/ml ATV 300/rtv 100 mg QD: ug/ml Survey of clinic patients on ATV and PPIs or H2B ATV Cmin levels available on 34 patients prior to intervention Suboptimal ATV levels observed, even with boosted ATV [Farthing et al. 7th ICTHI, P289]

9 Antacids: Dosing Atazanavir with Gastric Modifying Agents Give ATV 2 hours before/1 hr after Proton-pump inhibitors: AVOID COMBINATION H2-blockers: To achieve ATV levels 400 mg QD: dose ATV 10 hours after H2 blocker use ATV 300/rtv 100 mg QD To achieve ATV exposure 300/100 mg QD: Use ATV 400/rtv 100 mg QD

10 Plasma APV Concentration (ug/ml) Fosamprenavir +/- rtv May Be Coadministered with Esomeprazole Without Dose Adjustment FPV 1400mg BID + ESO 20mg QD, N=25 FPV 1400mg BID, N=25 FPV 700mg BID + RTV 100mg BID + ESO 20mg QD, N=23 FPV 700mg BID + RTV 100mg BID, N= Time (hours) [Shelton et al. 6th IWCPHT 2005, #24]

11 Gastric Modifying Agents and Protease Inhibitors ARV atazanavir Indinavir fosamprenavir tipranavir lopinavir/r, saquinavir, nelfinavir ddi tabs/antacids 89% Cmax, 87% AUC (space >1 hr apart) 84% (space >1 hr apart) 35% Cmax, 18% AUC (may give together) 25-29% in AUC, Cmax and C12 (space >1 hr apart) H2-blockers 41% AUC, 42% Cmin (NOT corrected with cola; give ATV 10 hrs after H2 or use ATV/r.) 7% Cmax, 2% AUC, 18% Cmin (clinically insig) 51% Cmax, 30% AUC, no change C12? (Use with caution.) PI kinetic parameters not affected. PPI 76% AUC, 78% Cmin (NOT corrected with RTV or acidic drink) 47% AUC, 55% Cmin (corrected when boosted with RTV 200mg) no effect on FPV steady-state PK (FPV or FPV/r)? (Use with caution.)

12 Tenofovir Interactions

13 Tenofovir-PI Interactions 50 PI AUC PI Cmin TDF AUC ATV 300mg ATV 300/rtv 100 FPV 1400/200 QD FPV 700/100 BID LPV 400/rtv 100 PIs not affected by TDF: IDV, NFV, RTV, TPV [6 th IWCPHT #10, 16, 32, 34, 55]

14 Potential for CD4 Decline with ddi/tenofovir Observed in various cohorts of patients virally suppressed on combination Declines of > cells in some by 1 year Predictors: weight, baseline CD4, ddi dose (400 mg>250 mg) [Negredo et al. AIDS 04, ICAAC 04 #H561, Karrer et al. CROI 05 #588 ] % Retrospective study: n=302, VL< 50 copies/ml, baseline CD cells/mm3 0 TDF+ddI (n=150) TDF (n=33) ddi (n=119) stable/increase > CD4 Drop from Baseline at Week 48 (cells/mm3)

15 Tenofovir Inhibits Purine Nucleoside Phosphorylase (PNP) PNP is a ubiquitous enzyme that catalyses the breakdown of endogenous purines and ddi: ddi concentrations intracellular concentrations of datp & dgtp impairs T-cell maturation & differentiation, apoptosis PNP deficiency (rare autosomal syndrome) causes cellular immunodeficiency disease may also lead to favoured incorporation of endogenous datp/dgtp by HIV-RT vs. purine NRTI-TP (i.e., efficacy of purine analogues such as ABC or ddi) [Kakuda et al. AIDS 2004;18: ]

16 CD4 Declines in Patients on Tenofovir Regimens without ddi Retrospective review of 103 subjects on TDF without ddi and VL<400 copies/ml 18/103 subjects (17%) had CD4 declines mean time on TDF 23 months (10-39), duration viral suppression 20 months (6-37) 56% on PI/rtv, 28% on 3-4 NRTIs alone Baseline CD4 395 ( ) Changes in CD4: Average 253 cells (-88 to -901) by 12 months (6-34) [Luber et al.6 th IWCPHT #53.]

17 Double PI Combinations

18 Atazanavir-PI Combinations Change vs. Baseline/Historical Controls 60% 40% 20% 0% -20% -40% -60% ATV Cmin ATV ATV ATV NFV BID LPV/r BID FPV 700/100 BID PI Cmin ATV 300/200 QD ATV 400/200 QD [6 th IWCPHT # 90, 56, 93, 91]

19 Other Double PI Boosting Attempts FPV 700/LPV 400/rtv mg BID: APV Cmin 72%, no change LPV NFV 1250/IDV 400/rtv 100 mg BID: N=16 Thai women therapeutic Cmin: 9/12 IDV, 12/12 NFV at 6 months, 6/16 D/C, 4/11 had VL<400 SQV 1600/rtv 100 vs. SQV /ATV 400 mg QD: Rtv>>ATV as booster SQV Cmin 87 vs. <30 ng/ml; no effect on ATV SQV 2000 mg + rtv 100 or keto 400 mg QD: Rtv >> keto as booster SQV Cmin 310 vs 40 ng/ml (target >100) [6 th IWCPHT # 69, 87, 89, CROI 655]

20 [Soy et al. 6th IWCPH #15; Almond et al. 6th IWCPH #19; Sheehan et al. 6th IWCPH #28; Friedland et al. CROI 2005, #891; Autar et al. 6th IWCPH #21] Efavirenz + TB Therapy PK interaction between EFV & RIF: 30% Cl, 25% Cmin, 22% AUC of EFV Recommend using EFV 800 mg with RIF However, several abstracts suggest that EFV 600 mg may provide therapeutic levels 2 retrospective surveys of TDM databases 1 prospective cohort study (n=17) Role for EFV TDM during TB therapy NVP observed with RIF in Thai cohort

21 Efavirenz Concentrations in the Presence of Rifampin Retrospective survey of HIV+ subjects taking RIF + EFV 600 mg or 800 mg (n=131) No difference in EFV levels between mg groups (median 2698 vs 2612 ng/ml) Retrospective survey of HIV+ subjects taking RIF + EFV 600 mg or 800 mg (n=16) No correlation between EFV levels and dose; all EFV conc. were therapeutic Efavirenz Concentrations (ng/ml) 800 mg EFV + RIF (n=111) P= mg EFV + RIF (n=20) Efavirenz Concentrations (mg/l) Median 3.9 mg/l 40% toxic 600 mg EFV + RIF (n=6) Median 2.9 mg/l 45.5% toxic 800 mg EFV + RIF (n=11) [Almond et al. 6th IWCPH #19] [Sheehan et al. 6th IWCPH #28]

22 Other Drug Interactions

23 Lopinavir/rtv Reduces Lamotrigine Exposure by 50% 4.5 Plasma concentration (geom mean) (mg/l) LTG day mg (n=15) BID (n=15) LTG 200 mg BID + LTG day 31 (n=15) LPV/r (n=15) LTG day mg (n=15) BID + LPV/r (n=15) Time after intake (hrs) [van der Lee et al. 6th IWCPH #12]

24 Paroxetine Exposure is 50% When Given with Fosamprenavir 700/rtv 100 mg BID Paroxetine Paroxetine + FPV/r paroxetine levels (mg/l) N=23 healthy volunteers time after intake (h) [Burger et al. 6th IWCPH #13]

25 Prenisolone Exposure Is Increased With Ritonavir 200 mg BID 400 Prednisolone Concentrations vs. Time Before and After Ritonavir Administration in Healthy Subjects (n=10) Concentration (ng/ml) Pre-ritonavir Ritonavir day 4 Ritonavir day % prednisolone AUC (p<0.002) Time (hr) [Penzak et al. 6th IWCPH #14]

26 Lopinavir/r + Rosuvastatin 14 subjects on LPV/r with VL<400 & TC >6.2 mmol/l were treated with rosuvastatin x 12/7 Rosuvastatin started at 10 mg/d, per lipid algorithm; dosage by week 12 was 20 mg (n=4) or 40 mg/d (n=10) LPV Cmin not affected by rosuvastatin Attempting to analyze rosuvastatin levels [van der Lee et al. 6th IWCPH #25]

27 Adherence

28 95% Adherence Not Necessary for NNRTI Regimens Recruited 109 patients (56 on single PIs, 53 on NNRTI), followed median 9.1 months Median 43.9 yrs, CD4 323, VL 2.5 log, 2 prior ARV regimens Adherence measured by unannounced pill count and electronic med monitoring Primary outcome was VL<400 copies/ml Bangsberg et al 12 th CROI 2005 # 616

29 NNRTI Regimens Can Lead to Viral Suppression at <95% Adherence Percent VL<400 copies/ml 100% 80% 60% 40% 20% 0% PI (single) NNRTI 0-53% 54-73% 74-93% % Adherence By Electronic Medication Monitoring (n=65) Near complete adherence improves the probability of durable viral suppression for all regimen types Bangsberg et al 12 th CROI 2005 # 616

30 Adherence to QD vs. BID Regimens N=237 N=245 Adherence: 93.5% QD vs. 84.5% BID, p< Pm dose missed more Consequence of missing 1 QD dose = missing 3 consecutive BID doses Such a delay was observed almost twice as often in the QD vs. BID frequently in BID arm groups [Vrijens et al. 6th IWCPH #3]

31 New Drugs

32 CCR5 Antagonists Maraviroc, MVC (Pfizer) (GSK) , SCH-D (SCH) Doses under study mg BID mg BID 5-15 mg QD, mg BID Metabolism 3A4, Pgp 3A4, 2C19 (minor), weak 3A inhibitor 3A4 Food effect 50% AUC AUC 47-63% Inducers AUC 70% (EFV, RIF) AUC 81% (EFV) Inhibitors AUC fold (PIs, keto) AUC 7.7 fold (LPV/r) AUC % (LPV, rtv) Tenofovir No interaction No interaction

33 Maraviroc + Metabolic Inhibitors 250 MVC 100mg BID MVC 100mg BID + Interactant MVC mg BID + Interactant 200 MVC Cmin (ng/ml) Placebo Kaletra TM Ritonavir (100mg BID) SQV/r (1000/100mg BID) Days Effect of P450 inhibitors can be corrected by dose adjustment (1/2 MVC dose) [Muirhead et al. 6th IWCPH #76]

34 Maraviroc + Metabolic Inducers mg BID MVC 100mg BID MVC + interactant 200mg BID MVC + interactant MVC Cmin (ng/ml) Placebo Efavirenz Rifampicin Day Effect of P450 inducers can be corrected by dose adjustment (2x MVC dose) [Muirhead et al. 6th IWCPH #76]

35 Maraviroc + PIs and EFV MVC plasma concentration (ng/ml) mg BID MVC + Kaletra (day 7) Kaletra + efavirenz (day 21) placebo (day 7) placebo (day 21) MVC plasma concentration (ng/ml) mg BID MVC + SQV/r (day 7) SQV/r + efavirenz (day 21) placebo (day 7) placebo (day 21) Time post dose (hours) Time post dose (hours) Efavirenz approximately halves the effect of the CYP3A4 inhibitors [Muirhead et al. 6th IWCPH #76]

36 TMC Drugs (Tibotec( Tibotec) TMC 114 (PI): 400/100 rtv mg BID No interaction with omeprazole 20 mg QD or ranitidine 150 mg BID TMC 125 (NNRTI): 800 mg BID Significant food effect (give with food) No interaction with ddi-ec (given 2 hrs before) TMC 278 (NNRTI): 25, 75, 150 mg QD Take with food ( AUC 45%) Tenofovir AUC 24%, Cmax 21%, Cmin 24%, no effect on TMC278 [Hoetelmans et al. 6th IWCPH #17, 29, 18]