Enzyme and Transporter Based Drug Interactions Progress and Future Challenges Regulatory Aspect of Drug Drug Interactions PDF

Drug-drug interactions AAPS/ISSX WorkshopSatellite Program of 2007 AAPS Annual Meeting November 10, 2007, San Diego, CA Factors Affecting Exposure/Drug Effects Intrinsic factors Age Gender Disease Pregnancy/Lactation Race Genetics Enzyme- and Transporter-Based Drug Interactions: Progress and Future Challenges: Extrinsic factors Drug-drug interaction Smoking/Diet Environmental Medical Practice/ Regulatory Regulatory Aspect of Drug-Drug Interactions Shiew-Mei Huang, Ph.D. Deputy Director Office of Clinical Pharmacology CDER, FDA shiewmei.huang@fda.hhs.gov Organ Dysfunction 1 Adapted from ICH E5, 1998: http://www.fda.gov/cder/guidance/2293fnl.pdf 2 Drugs withdrawn from the US Market due to Safety reason: Withdrawn Approv Adverse Drug Reactions­ • 100,000- ADR-related deaths yearly • 2,000,000- serious ADRs yearly < JAMA 1998;279:1200–1205; Arch Intern Med 1995;155(18):1949–1956> Drug name Mibefradil Bromfenac Terfenadine Astemizole Alosetron* Cisapride Cerivastatin Use High blood pressure/Chronic stable angina Risk Torsades de Pointes; Drug-drug interactions; Acute liver failure Torsades de Pointes; Drug-drug interactions Torsades de Pointes; Drug-drug interactions Torsades de Pointes Torsades de Pointes; Drug-drug interactions Acute liver failure Rhabdomyolysis; Drug-drug interactions Bronchospasm Fatal arrhythmia Heart attack; stroke Skin reactions (SJS) Brain infection Cardiopulmonary arrest Liver failure 3 1998 1998 1998 1999 1999 2000 2000 2001 2001 2003 2004 2005 2005 2005 1997 1997 1985 1988 1997 1993 1997 1997 1999 1993 1999 2001 2004 1975 NSAID Antihistamine Antihistamine Grepafloxacin Antibiotics Heartburn Cholesterol lowering 2000(2002)* 2000 Irritable bowel syndrome in women Ischemic colitis; complications of constipation Troglitazone Diabetes Rapacuronium Anesthesia Levomethadyl Opiate dependence Rofexocib Valdecoxib 99m Tc** Pemoline Pain relief Pain relief Diagnostic aid ADHD 2005(2006)* 2004 Natalizumab* Multiple sclerosis - Inappropriate use of drugs Inadequate monitoring Other preventable causes “Idiosyncratic” 4 * remarketed with restricted distribution ** Technetium (99m Tc) fanolesomab Discussions on Drug Interactions • Publications of in vitro and in vivo drug interaction guidance documents - http://www.fda.gov/cder/guidance/clin3.pdf (1997) - http://www.fda.gov/cder/guidance/2635fnl.pdf (1999) • Advisory Committee meetings - April 20, 2003 (CYP3A inhibitor classification and P-gp inhibition) - November 18, 2003 (CYP2B6 and CYP2C8- related interactions) - [October, 2004, Concept paper published] November 3, 2004 (relevant principles of drug interactions) - [September, 2006, draft guidance published] October, 2006 (transporter based interactions) 5 Draft published for public comment September 11, 2006 http://www.fda.gov/cde r/guidance/6695dft.pdf 6 Shiew-Mei Huang, AAPS-ISSX Workshop, November 10, 2007, San Diego, CA Drug-drug interactions Key messages 1. Metabolism, transport, drug-interaction info key to benefit/risk assessment 2. Integrated approach (in vitro and in vivo) may reduce number of unnecessary studies and optimize knowledge 3. Study design/data analysis key to important information for proper labeling October 2006, advisory committee meeting: http://www.fda.gov/ohrms/dockets/ac/cder06.html#PharmScience http://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4248s1-index.htm 7 Key messages (2) 4. Clinical significance of a PK-based interaction needs to be interpreted based on exposure-response data/analyses 5. Classification of CYP inhibitors and substrates can aid in study design and labeling 6. Labeling language needs to be useful and consistent (new labeling rule, effective June 2006) 8 What’s New? CYP Enzymes Major CYPs (1A2, 2C8, 2C9, 2C19, 2D6, 3A) 2B6 -specific substrates -specific inhibitors -inducers In vitro and in vivo Transporters P-gp - specific substrate - general inhibitors - inducers in vitro and in vivo Others transporters: OATP, BCRP, MRP2, OATs, OCTs -general substrates, inhibitors, inducers (in vitro/in vivo) 9 What’s New? CYP Enzymes Transporters (P-gp) Decision trees-­ when in vivo studies are recommended per in vitro data - substrate (flux ratio) - inhibitor (I/Ki) - (inducer) No classification system recommended A decision tree --­ triggers when in vivo studies are recommended per in vitro data - substrate - inhibitor (I/Ki > 0.1) - inducer (40% control) Classification of -inhibitors -substrates < September 2006 guidance- http://www.fda.gov/cder/guidance/6695dft.pdf> 10 OCPB GRP In Vitro Metabolism Data for each key CYP enzyme Substrate? No Yes/ unknown Number of published papers/patents 600 500 400 No MDR1 Inhibitor/ inducer? Yes/ unknown StopPathway General Labeling* Major? No Yes/ unknown In vivoMost Sensitive Substrates StopGeneral Labeling* • Obviate certain in vivo metabolic interaction studies • Focused in vivo investigations 11 300 200 100 0 76 81 86 91 Year 96 '01 '06 12 (Huang, S-M, Advisory committee, http://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4248s1-index.htm) BCRP OCT MRP2 OAT OATP1B1 StopGeneral Labeling* *Population PK studies < Huang, S-M, et al, J Clin Pharmacol> > In vivoMost Potent Inhibitor/inducer Shiew-Mei Huang, AAPS-ISSX Workshop, November 10, 2007, San Diego, CA Drug-drug interactions Figure 1. Decision tree to determine whether an investigational drug is an inhibitor for P-gp and whether an in vivo drug interaction study with a P-gp substrate is needed Bi-directional transport assay Alternate [I] [I]/Ki > 10 See poster by Lei Zhang AM-07-01722 Drugs that showed significant in vivo inhibition on digoxin In Vivo Interaction Data Data Used for Prediction Cmax at steadystate (µM) 2.8 50% 44% 46% 75% 44% 37% 45% 59% 39% 60% 46% 50% 51% 0.95 4.5 8.56 5.35 0.13 0.17 0.644 0.460 Net flux with concn of drug Net flux with concn of drug Compound Cyclosporin % Increase in Cmax 44% % Increase in AUC Gut Conc. (µM) 1167 1134 1022 9357 2674 704 532 1100 230 IC50* (µM) 1.64 1.34 16 197 >1004 5.94 74 264 > 1004 [I](1)/IC50 1.75 0.73 0.28 0.043 <0.054 0.022 0.024 0.0024 < 0.0046 [I](2)/IC50 729 872 64 47.5 <26.7 119 76.0 4.17 < 2.30 14 Determine Ki or IC50 [I]/IC50 (or Ki) > 0.1 An in vivo interaction study with a P-gp substrate (e.g., digoxin) is recommended Poor or non-inhibitor Itraconazole Quinidine [I]/IC50 (or Ki) < 0.1 An in vivo interaction study with a P-gp substrate is not needed 13 Ranolazine Clarithromy cin Verapamil Diltiazem Talinolol Captopril Drugs that did not show significant in vivo inhibition on digoxin In Vivo Interaction Data Data Used for Prediction Cmax at steadystate (µM) 0.049 0.017 Figure 2. Decision tree to determine whether an investigational drug is a substrate for P-gp and whether an in vivo drug interaction study with a P-gp inhibitor is needed Alternatively, use a % value (relative to a probe substrate) Bi-directional transport assay Net flux ratio < 2 Poor or non-substrate Net flux Ratio > 2 Gut Conc. (µM) 265 160 IC50* (µM) > 1004,5 >1005 [I](1)/IC50 < 0.00049 <0.00017 [I](2)/IC50 < 2.65 <1.60 Compound Atorvastatin Rosuvastatin % Increase in Cmax 20% 4% % Increase in AUC 15% 4% Is efflux significantly inhibited by 1 or more P-gp inhibitors YES Likely a P-gp substrate An in vivo interaction study with a P-gp inhibitor may be Note warranted exceptions NO Other efflux transporters are responsible Losartan 13% 6% 0.49 156 0.0031 2.78 Omeprazole Sitagliptin 10% 18% 11% 4.42 0.95 463 765 100 > 500 0.044 < 0.0019 4.63 < 1.53 15 Further in vivo to determine which efflux transporters are involved may be warranted 16 What’s New? • protocol restriction (juice, dietary supplement use) • multiple- inhibitor study trigger • cocktail approach Comments Received 22 comments in the docket­ - PhRMA, JPMA - 15 individual companies - 3 contract labs - 2 individuals Others (emails, informal meetings) 17 26 Sitagliptin (Januvia®) Cases Drug interactions evaluated? Clinical significance (exposure-response)? Labeling language? 27 • Absolute %F ~ 87%; 73% excreted unchanged in urine; Renal clearance 350 mL/min; T 1/2~ 12 hours; 38% protein-binding. • Linear PK (25-400/600 mg); no food effect on PK; Cmax~ 1 uM after 100 mg dose • Metabolism by CYP3A/CYP2C8 • In vitro (effect on CYPs): - IC50 100 uM- CYP1A2, 2B6, 2D6, 2C9, 2C19, 3A4 (I/Ki <0.01- not an inhibitor) - Induction - <13% of CYP3A control (not an inducer) • In vitro: substrate of P-gp and OAT-3 (not OCT2, OAT1, PEPT1); not an inhibitor of P-gp 28 Figure 1. Decision tree to determine whether an investigational drug is an inhibitor for P-gp and whether an in vivo drug interaction study with a P-gp substrate is needed Bi-directional transport assay Alternate [I] [I]/Ki > 10 See poster by Lei Zhang AM-07-01722 Figure 2. Decision tree to determine whether an investigational drug is a substrate for P-gp and whether an in vivo drug interaction study with a P-gp inhibitor is needed Bi-directional transport assay Net flux ratio < 2 Poor or non-substrate Net flux with concn of drug IC50> 500 uM Net flux with concn of drug I/IC50: Net flux Ratio > 2 Is efflux significantly inhibited by 1 or more P-gp inhibitors YES Likely a P-gp substrate Determine Ki or IC50 [I]/IC50 (or Ki) > 0.1 An in vivo interaction study with a P-gp substrate (e.g., digoxin) is recommended I: 1uM @100 mg Poor or non-inhibitor <1.5 <0.002 Ialternate/IC50: [I]/IC50 (or Ki) < 0.1 An in vivo interaction study with a P-gp substrate is not needed 29 High Other efflux transporters are responsible %F NO An in vivo interaction study with a P-gp inhibitor may be Note warranted exceptions Further in vivo to determine which efflux transporters are involved may be warranted 30 Shiew-Mei Huang, AAPS-ISSX Workshop, November 10, 2007, San Diego, CA Drug-drug interactions Sitagliptin on digoxin Digoxin+S/Digoxin 1.24 1.22 1.2 1.18 1.16 1.14 1.12 1.1 1.08 1.06 1.04 Sitagliptin (Januvia®) • Efficacy - Preclinical data indicated 80% DPP-4 inhibition for PD effect - Phase 1 in Healthy subjects – 25-600 mg study; DPP­ 4 inhibition-> 100 mg maintained 80% inhibition - Phase 2: 25-100 mg BID or QD-> HbA1c - Phase 3: 100 and 200 mg QD study; HbA1c, FPG, PPG • Safety - QT prolongation: -Healthy subjects: 100 and 800 mg vs. placebo vs. Moxifloxacin; patients 100, 200 mg No effect boundary 50-200% 31 Exposure-response data AUC 100 mg 200 mg 100 mg Cmax 200 mg http://www.fda.gov/cder/foi/nda/2006/021995s000_MedR.pdf> 32 Fold-Change in Exposure (AUC) Sitagliptin (Januvia®) Exposure-response data • Healthy subjects (n=79) 100 and 800 mg vs. placebo vs. Moxifloxacin 7-14 msec QTcFChange from Baseline (active-placebo) 14 12 10 8 6 4 2 0 -2 0 5 10 15 4 3 .5 3 2 .5 2 1 .5 1 0 .5 0 Labeling: Dosage & Administration Age >65 Renal CrCl Moxifloxacin 8 msec Race Gender Metformin Hepatic Child-Pugh 7-9 Cyclosporine Control 800 mg 50-80 100 mg Shallow “concentration- QTcF change” curve 33 100 mg daily 30-50 50 mg daily <30; ESRD/HD < October 2006 sitagliptin (JANUVIA ® -Merck) labeling> http://www.fda.gov/cder/foi/label/2006/021995lbl.pdf 25 mg daily 34 Fold-Change in AUC Fold-Change in AUC Labeling: Effect of Other Drugs on Sitagliptin 2 1.8 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0 Labeling: Effect of Sitagliptin on Other Drugs 2 1.8 Warfarin \ 1.6 Contrvol Rosiglitazone Glyburide 1.4 OC Digoxin 1.2 NE/EE Simvastatin Metformin 1 0.8 0.6 0.4 0.2 0 Cyclosporine Control 600 C, 100 S Single dose ..did not meaningfully alter PK Metformin ..meaningful interactions …not expected with other P-gp inhibitors < Data from October 2006 sitagliptin (JANUVIA ® -Merck) labeling> http://www.fda.gov/cder/foi/label/2006/021995lbl.pdf 35 Clinical Pharmacology Section Not ­ CYP2C8 inhibitor monitored Not ­ Risk of Not ­ Did not appropriately hypoglycemic OCT CYP3A meaningfully (Drug effect unknown inhibitor inhibitor alter….. Interactions) (Warnings/ minimal effect Precautions) Not ­ CYP2C9 Inhibitor/ PMC 36 Shiew-Mei Huang, AAPS-ISSX Workshop, November 10, 2007, San Diego, CA Drug-drug interactions Lapatinib (Tykerb®) • 1500 mg daily undivided dose • Metabolized by CYP3A (major) and CYP2C8/CYP2C19 • Ketoconzole increased exposure 3.6-fold • Carbamazepine decreased exposure by 72% • Possible inhibitor of CYP2C8 and CYP3A • I/Ki= 9.2 (CYP2C8), 5.0 (CYP3A) Postmarketing Study Commitment (PMC) •A study with midazolam to evaluate CYP3A inhibition effect at steady state dosing •A study with paclitaxel or rosiglitazone to evaluate CYP2C8 inhibition effect •A study with digoxin to evaluate P-gp inhibition effect • http://www.fda.gov/cder/foi/appletter/2007/022059s000ltr.pdf 38 • P-gp substrate, flux ratio of 15.6 at Cmax • inhibits P-gp (I/IC50= 1.4) August 2007 lapatinib (Tykerb) label http://www.fda.gov/cder/foi/label/2007/022059s002lbl.pdf 37 Highlights of Prescription Information •DRUG INTERACTIONS •TYKERB is likely to increase exposure to concomitantly administered drugs which are metabolized by CYP3A4 or CYP2C8. (7.1) •Avoid strong CYP3A4 inhibitors. If unavoidable, consider dose reduction of TYKERB in patients coadministered a strong CYP3A4 inhibitor. (2.2, 7.2) Full Prescription Information 7.1 Effects of Lapatinib on Drug Metabolizing Enzymes and Drug Transport Systems Lapatinib inhibits human P-glycoprotein. If TYKERB is administered with drugs that are substrates of Pgp, increased concentrations of the substrate drug are likely, and caution should be exercised. 7.3 Drugs that Inhibit Drug Transport Systems Lapatinib is a substrate of the efflux transporter P-glycoprotein (Pgp, ABCB1). If TYKERB is administered with drugs that inhibit Pgp, increased concentrations of lapatinib are likely, and caution should be exercised. 40 •Avoid strong CYP3A4 inducers. If unavoidable, consider gradual dose increase of TYKERB in patients coadministered a strong CYP3A4 inducer. (2.2, 7.2) 39 Summary • CYP-based interactions (effect on others and others on NME) need to be routinely evaluated - labeling recommendations (language and section) need to be based on exposureresponse relationship & benefit/risk ratio - measures to improve labeling consistency have been proposed - other non-CYP enzyme based interactions have been increasingly evaluated; need standardized procedure 41 Summary (2) • Transporter-based interactions (effect on others and others on NME) have been increasingly evaluated - P-gp-based interactions are among the most evaluated; standardized procedure (both in vitro & in vivo) have been recommended • Need standardized procedure for other transporters (BCRP, OATP1B1, OAT, OCT) 42 Shiew-Mei Huang, AAPS-ISSX Workshop, November 10, 2007, San Diego, CA Drug-drug interactions Drug Interactions working group Sophia Abraham Sang Chung Shiew-Mei Huang Patrick Marroum Nam Atik Rahman Sally Yasuda Jerry Collins David M Green Hon Sum Ko Robert Temple Kenneth Thummel (on sabbatical at FDA, 2006) Acknowledgement Sayed Al-Habet Philip Colangelo Ron Kavanagh Srikanth Nallani Kellie Reynolds Acknowledgement (2) Lei K Zhang Soloman Sobel David Frucht Toni Stifano Janet Norden Raman Baweja Paul Hepp Lawrence Lesko Wei Qiu Xiaoxiong Wei Jenny H Zheng John Strong Gilbert Burckart 43 44 References • Guidance for Industry: Drug Interaction Studies- Study Design, Data Analysis and Implications for Dosing and Labeling. http://www.fda.gov/cder, http://www.fda.gov/cder/guidance/6695dft.pdf, Draft published in September 2006 [last accessed October 6, 2007]. http://www.fda.gov/CDER/drug/drugInteractions/default.htm Backup slides • FDA Drug Development and Drug Interactions website. [last accessed October 6, 2007] • Huang S-M, Temple R, Throckmorton DC, Lesko L: Drug – drug interactions: study design, data analysis and implications for dosing recommendations, Clin Pharmacol Ther 2007; Feb; 81(2): 298-304. 45 46 AUC change of a drug (fold) AUC change of drug (fold) Liver Sinusoidal Hepatic Uptake: OCT1, OATP-C, OATP-B, OATP8, NTCP, OAT2 Secretion: MRP1, MRP3 Brain Transporters: P-gp (MDR1), OAT3, OATP-A, MRP1, MRP3 Multiple inhibition 25.0 Maximum change by CYP1 and 2 inhibition Liver Canalicular Biliary Excretion: P-gp, MRP2, BCRP, MDR3 20.0 15.0 Potential surprise! Change by CYP 2 inhibition Prediction from CYP 1 and CYP2 inhibition Change Change by CYP 1 inhibition inhibition Intestinal Luminal Absorption: PEPT1 Secretary: P-gp, OATP3 Kidney Basolateral: OCT1, OCT2, OAT1, OAT2, OAT3, MRP1 10.0 5.0 Kidney Apical Renal Secretion: P-gp, OAT4 Reabsorption: PEPT2 0.0 0 0.2 Fractional CL by CYP 1 0.4 0.6 0.8 1 Relative contribution of Relative contribution of CYP 1 CYP 1 and 2 is equal. and 2 is equal. 47 Thummel K, Chung, S, et al, ASCPT, poster II-77, March 23, 2007 48 Shiew-Mei Huang, AAPS-ISSX Workshop, November 10, 2007, San Diego, CA Drug-drug interactions Darunavir (Prezista®) • 600mg/100 mg bid, co-administered with ritonavir • Absolute %F ~ 37% (without ritonavir); 82% (with ritonavir) ; t1/2 15 hours (with ritonavir) • Metabolism by CYP3A; ritonavir increased exposure by 14-fold Table 4: Drug Interactions: Pharmacokinetic Parameters for Darunavir in the Presence of Co-Administered Drugs LS Mean Ratio % (90% CI) of Darunavir Pharmacokinetic Parameters With/Without Co-Administered Drug No Effect =1.00 Dose/Schedule CoAdministered Drug ˆ q.d. N PK CoAdministered Drug Darunavir/ rtv C max AUC C min N = number of subjects with data; – = no information available. = daily = twice daily based on between-study comparison. † b.i.d. ‡ Ratio Co-Administration With Other Protease Inhibitors Atazanavir Indinavir Lopinavir/ Ritonavir Saquinavir hard gel capsule 300 mg q.d. ˆ 400/100 mg b.i.d. † 400/100 mg b.i.d. 300/100 mg b.i.d. 400/100 mg b.i.d. 13 9 9 14 ↔ ↑ ↓ ↓ 1.02 (0.96–1.09) 1.11 (0.98–1.26) 0.61 (0.51–0.74) 0.83 (0.75–0.92) 1.03 (0.94–1.12) 1.24 (1.09–1.42) 0.47 (0.40–0.55) 0.74 (0.63–0.86) 1.01 (0.88–1.16) 1.44 (1.13–1.82) 0.35 (0.29–0.42) 0.58 (0.47–0.72) 800 mg b.i.d. 400/100 mg b.i.d. 1000 mg b.i.d. Co-Administration With Other Antiretrovirals Efavirenz 49 Nevirapine 600 mg q.d. 200 mg b.i.d. 300/100 mg b.i.d. 400/100 mg b.i.d. 12 8 ↓ ↑ 0.85 (0.72–1.00) 1.40 ‡ (1.14–1.73) 0.87 (0.75–1.01) 1.24 ‡ (0.97–1.57) 0.69 (0.54–0.87) 50 1.02 ‡ (0.79–1.32) CONTRAINDICATIONS Co-administration of PREZISTA/rtv is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). These drugs are listed in Table 9 (also see PRECAUTIONS, Drug Interactions , Table 10). Table 9: Drugs That Are Contraindicated With PREZISTA/rtv Drug Class Drugs Within Class That Are Contraindicated With PREZISTA/rtv Astemizole, Terfenadine Dihydroergotamine, Ergonovine, Ergotamine, Methylergonovine Cisapride Pimozide Midazolam, Triazolam Precautions Drug Interactions PREZISTA and ritonavir are both inhibitors of CYP3A. Co-administration of PREZISTA and ritonavir with drugs that are primarily metabolized by CYP3A may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events (see Tables 10 and 11). Drugs that are contraindicated and not recommended for co-administration with PREZISTA/rtv are included in Table 10. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy. Antihistamines Ergot Derivatives GI Motility Agent Neuroleptic Sedative/hypnotics Due to the need for co-administration of PREZISTA with 100 mg of ritonavir, please refer 51 to ritonavir prescribing information for a description of ritonavir contraindications. 52 Table 10: Drugs That Should Not Be Co-Administered With �PREZISTA/rtv Drug Class: Drug Name Anticonvulsants: Carbamazepine, phenobarbital phenytoin Antihistamines: astemizole, terfenadine Antimycobacterial: rifampin Ergot Derivatives: dihydroergotamin e, ergonovine, ergotamine, methylergonovine Gastrointestinal Motility Agent: cisapride Herbal Products: St. John’s wort ( Hypericum perforatum ) HMG-CoA Reductase Clinical Comment Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. PREZISTA/rtv should not be used in combination with phenobarbital, phenytoin, or carbamazepine as co-administration may cause significant decreases in darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA. CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. Rifampin is a potent inducer of CYP450 metabolism. PREZISTA/rtv should not be used in combination with rifampin, as this may cause significant decreases in darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA. CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. Table 11: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction (See CLINICAL PHARMACOLOGY for Magnitude of Interaction, Tables 4 and 5) Concomitant Drug Class: Drug Name Effect on Concentration of Darunavir or Concomitant Drug Clinical Comment HIV-Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Efavirenz ↓ darunavir ↑ efavirenz Co-administration of darunavir/rtv and efavirenz decreased darunavir AUC by 13% and C min by 31%. The AUC of efavirenz increased by 21% and C min increased by 17%. The clinical significance has not been established. The combination of PREZISTA/rtv and efavirenz should be used with caution. PREZISTA/rtv and nevirapine can be coadministered without any dose adjustments. It is recommended that didanosine be administered on an empty stomach. Therefore, didanosine should be administered one hour before or two hours after PREZISTA/rtv (which are administered with food). ↔ darunavir ↑ tenofovir PREZISTA/rtv and tenofovir disoproxil fumarate can be co-administered without any dose adjustments. 54 Nevirapine ↔ darunavir ↑ nevirapine HIV-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs) CONTRAINDICATED due to potential for serious and/or lifethreatening reactions such as cardiac arrhythmias. PREZISTA/rtv should not be used concomitantly with products containing St. John’s wort ( Hypericum perforatum ) because co-administration may cause significant decreases in darunavir plasma concentrations. 53 This may result in loss of therapeutic effect to PREZISTA. Potential for serious reactions such as risk of myopathy including Didanosine Tenofovir Disoproxil Fumarate Shiew-Mei Huang, AAPS-ISSX Workshop, November 10, 2007, San Diego, CA Drug-drug interactions Maraviroc (Selzentry®) • 150-600 mg bid • Absolute %F ~ 23% (100 mg)-33% (300 mg) • substrate of CYP3A and P-gp • CYP3A/Pgp inhibitors ketoconazole, lopinavir/ritonavir, ritonavir, saquinavir and atazanavir increased maraviroc Cmax and AUC • CYP3A inducers rifampin and efavirenz decreased maraviroc Cmax and AUC. • Tipranavir/ritonavir (net CYP3A inhibitor/Pgp inducer) did not affect the steady state mraviroc PK August 2007 maraviroc (Selzentry®) labeling; http://www.fda.gov/cder/foi/label/2007/022128lbl.pdf> • Maraviroc is unlikely to inhibit ….(CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A) because ..did not inhibit … in vitro • Maraviroc had no effect on the PK of zidovudine or lamivudine .. midazolam, ethinylestradiol and levonorgestrel, urinary 6β-hydroxycortisol/cortisol ratio • Potential inhibition of CYP2D6 at higher dose 56 55 Varenicline- in vitro • In vitro studies demonstrated that varenicline does not inhibit human renal transport proteins at therapeutic concentrations. Therefore, drugs that are cleared by renal secretion (e.g. metformin -see below) are unlikely to be affected by varenicline. • In vitro studies demonstrated the active renal secretion of varenicline is mediated by the human organic cation transporter, OCT2. Co­ administration with inhibitors of OCT2 may not require a dose adjustment …. as the increase in systemic exposure .. is not expected to be clinically meaningful (see Cimetidine interaction below). 57 Varenicline (2)- in vivo • Metformin: varenicline .. did not alter the steady-state pharmacokinetics of metformin .. which is a substrate of OCT2. Metformin had no effect on varenicline steady-state pharmacokinetics. • Cimetidine: Co-administration of an OCT2 inhibitor, cimetidine … with varenicline (2 mg single dose) … increased the systemic exposure of varenicline by 29% .. due to a reduction in varenicline renal clearance. 58 Shiew-Mei Huang, AAPS-ISSX Workshop, November 10, 2007, San Diego, CA