SOT3_DDI and PGx_53.pptx

Solid Organ Transplantation Pharmacogeno mics and DrugDrug Interactions Yasar Tasnif, PharmD, BCPS, FAST Associate Professor of Practice | UTEP School of Pharmacy Objectives • Pharmacogenomics • Identify pathways of metabolism for immunosuppressants • Identify genetic variants that have been assoc...

Solid Organ Transplantation Pharmacogeno mics and DrugDrug Interactions Yasar Tasnif, PharmD, BCPS, FAST Associate Professor of Practice | UTEP School of Pharmacy Objectives • Pharmacogenomics • Identify pathways of metabolism for immunosuppressants • Identify genetic variants that have been associated with medications used in Transplantation • Review how data from genetic studies in certain disease states apply to clinical practice • Drug-Drug Interactions • Identify common drug-drug interactions in transplant recipients Definitions • Pharmacogenetics • Relationship between single-gene variation and drug response or toxicity • Pharmacogenomics • Relationship between multi-gene variations and drug response or toxicity • Polymorphisms • Mutations that occur in >1% of the population • SNPs – Substitution of one nucleotide base for another • Most common type of gene variation Pharmacogenomics Handbook, Lexi-Comp © 2003 Sources of Variability in Kinetics • Variability impacts clinical care when utilizing drugs with a narrow therapeutic index • Some causes of inter and intra-individual variability in CNI pharmacokinetics • Patient age, body weight, primary disease, liver function, post-operative period, infectious disease, food, diarrhea, concomitant drugs • Polymorphic expression of enzymes and transporters implicated in the disposition of CNIs • Other factors Masuda S., K. Inui. Pharmacol Ther. 2006; 112(1):184-98 The Effects of P-gp and CYP3A4/5 on CNIs Masuda S., K. Inui. Pharmacol Ther. 2006; 112(1):184-98 Pharmacogenomics How We Think We Can Use Genomics to Tailor Drug Therapy https://elcaminogmi.dnadirect.com/img/content/common/ pharmacogenetics.gif CYP3A5, CYP3A4, and Pglycoprotein • Contribute to the bioavailability and metabolism of tacrolimus, cyclosporine, and sirolimus • All exhibit genetic polymorphisms • May contribute to the inter-individual variation in the pharmacokinetics of tacrolimus, cyclosporine and sirolimus Le Meur et al. Clin Pharmacol Ther. 2006; 80(1): 51-60 Fredericks et al. Am J Pharmacogenomics. 2003; 3(5): 291-301 Hesselink et al. Clin Pharmacol Ther. 2003; 74(3): 245-54 Polymorphic Expression of P-glycoprotein • The MDR1 gene is located at chromosomal band 7q21.1 • MDR1 alternatively called ABCB1 • Encodes an ATP-driven efflux pump, Pglycoprotein Pal D., A.K. Mitra. Life Sci. 2006; 78(18): 2131-45 Masuda S., K. Inui. Pharmacol Ther. 2006; 112(1): 184-98 Polymorphic Expression of CYP3A5 • An SNP in intron 3 of the CYP3A5 gene causes a splicing error and aberrantly spliced mRNA with a premature stop codon • CYP3A5*6 causes an alternative splicing and produces a truncated protein • CYP3A5*7 causes a frameshift mutation and a premature stop codon Fig. a – Splice variants of CYP3A5 • These SNPs result in significantly reduced enzyme expression Kuehl et al. Nat Genet. 2001; 27(4): 383-91 Polymorphic Expression of CYP3A5 • CYP3A5 may represent up to 50% of the total hepatic CYP3A content in people who are CYP3A5*1/*3 or CYP3A5*1/*1 • This gene may be an important genetic contributor to inter-individual and inter-racial differences in CYP3Adependent drug clearance Kuehl et al. Nat Genet. 2001; 27(4): 383-91 Differential Metabolism of Immunosuppressants by CYP3A4 and CYP3A5 (in Vitro) Tacrolimus 0.25 0.20 0.15 0.10 0.05 0.00 CYP3A4 Elimination Rate Constant (min -1) 3 2 Elimination Rate Constant (min -1) Elimination Rate Constant (min -1) 1 CYP3A5 Cyclosporine 0.25 0.20 0.15 0.10 0.05 0.00 CYP3A4 CYP3A5 Sirolimus 0.25 Figures 1-3 – Substrate disappearance over time. Substrate (0.2 µM) was incubated with recombinant CYP3A4, and CYP3A5 with co-expressed b5 supersomes. Incubation stop times were at 0, 3, 6, and 10 minutes. No NADPH was used as a control with 0, and 10 minute stop times. 0.20 0.15 0.10 0.05 0.00 CYP3A4 CYP3A5 Uridine Glycosyltransferases (UGT) • Mycophenolic acid (MPA) has the greatest number of gene polymorphisms associated with both its disposition in the body and its immunosuppressive effect. • Several UGTs metabolize MPA, and the UGTs are polymorphic. • Two SNPs in UGT1A9 have been associated with lower overall exposure to MPA, as measured by plasma concentrations, in renal transplant recipients and normal subjects. Burckart GJ. Pharmacogenomics: the key to improved drug therapy in transplant patients. Clin Lab Med. 2008 Sep;28(3):411-22 Inosine monophosphate dehydrogenase (IMPDH) • The activity of MPA is derived from its inhibition of inosine monophosphate dehydrogenase (IMPDH). • IMPDH is encoded by two separate genes, IMPDH1 and IMPDH2. The IMPDH1 gene is more polymorphic. • Reports suggest that IMPDH polymorphisms could play a part in the activity of MPA. • Overall effect of the administration of MPA is mediated by metabolizing enzymes, membrane transporters, and the target enzyme in purine synthesis, all of which are polymorphic in nature. Burckart GJ. Pharmacogenomics: the key to improved drug therapy in transplant patients. Clin Lab Med. 2008 Sep;28(3):411-22 Existing high or low activity of enzyme may determine rejection or toxicity Increase in activity leads to decrease in MPA exposure Murray, B., Hawes, E., Lee, R., Watson, R., & Roederer, M. W. (2013). Genes and beans: Pharmacogenomics of renal transplant. Pharmacogenomics, 14(7), 769-98. Genomics and Adverse Drug Reactions • CNI-mediated nephrotoxicity remains a serious problem • A single mediator in initiation and/or progression of nephropathy remains to be elucidated • Cyclosporine and tacrolimus nephrotoxicity is dosedependent • CNI-mediated nephrotoxicity may be due to intrarenal accumulation of parent drug • Christians et al., state that conversion of parent drug to metabolite can serve as a protective mechanism from damage to the kidney • CYP3A5 expression in the kidney may have less nephrotoxicity Baran et al. Am J Cardiovasc Drugs 2004; 4(1): 21-9 Christians et al. Eur J Clin Pharmacol. 1991; 41(4):285-90 Olyaei et al. Curr Opin Crit Care. 2001 2001; 7(6): 384-9 Mihatsch et al. Clin Nephrol 1998; 49(6): 356-63 Effect of CYP3A5 Gene Variation on Systemic and Intra-renal Tacrolimus Disposition • Tacrolimus was administered orally to 24 healthy volunteers who were selected on the basis of their CYP3A5 genotype • The simulated tacrolimus exposure in the renal epithelium • Simulated tacrolimus amount in the renal epithelium • Logarithmic amount shown in the upper Zheng S et al. Measurement and compartmental modeling of the effect of CYP3A5 gene variation on systemic and intrarenal tacrolimus insert disposition. Clin Pharmacol Ther. 2012 Dec; 92(6):737-45. Genomics and Solid Organ Transplantation • Polymorphic expression of CYP3A5, and possibly CYP3A4 and P-glycoprotein are a significant cause of inter-individual variability in CNI pharmacokinetics • Prospective genotyping for CYP3A5 may be beneficial for tacrolimus and sirolimus initial dose selection • Current literature supports individualizing initial tacrolimus treatment using CYP3A5 genotype (i.e. increasing starting dose to 1.5-2 times recommended starting dose). • CYP3A5 genotyping might also be of some clinical value in predicting the risk of CNI-induced nephrotoxicity • May help with medication selection for patients with a higher risk for renal dysfunction Birdwell KA et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing. Clin Pharmacol Ther. 2015; 98(1):19-24. CYP3A5 and Sirolimus Oral Clearance – Le Meur et al. CYP3A5*3*3 CYP3A5*1*1/*1*3 Le Meur et al. Clin Pharmacol Ther. 2006; 80(1): 51-60 Long-Term Clinical Impact of Adaptation of Initial Tacrolimus Dosing to CYP3A5 Genotype CYP3A5 Genotype Primary End Point Success 1 Control Group (n=104) Adapted Dose Group (n=108) p value *1*1 6 (5.5) 4 (3.5) 0.4 *1*3 15 (14.5) 22 (20) *3*3 83 (80) 82 (42) 26 (25) 46 (42) 0.01 1 Tacrolimus trough within the target range of concentration (10–15 ng/mL) 10 days after transplantation. • The Tactique study, a prospective and multicenter trial, was conducted in 2006 and 2007 to evaluate whether adaption of tacrolimus dosing according to CYP3A5 genotype would allow earlier achievement of target tacrolimus trough levels in kidney transplant recipients. • Successful in achieving target concentrations earlier. However, BPAR and graft survival were similar between groups. Pallet et al. Long-Term Clinical Impact of Adaptation of Initial Tacrolimus Dosing to CYP3A5 Genotype. American Journal of Transplantation 2016; 16: 2670–2675 ASERTAA Trial - Pharmacogenetic Study of IR Vs. Extended-Release Tacrolimus in African American Kidney Transplant Recipients • • Observed mean tacrolimus whole blood time-concentration curves by CYP3A5 expresser status for IRTac. With IR-Tac, tacrolimus Cmax was 33% higher in CYP3A5 expressers compared with nonexpressers (p= 0.04). Trofe-Clark J et al. Results of ASERTAA, a Randomized Prospective Crossover Pharmacogenetic Study of Immediate-Release Versus Extended-Release Tacrolimus in African American Kidney Transplant Recipients. Am J Kidney Dis. 2018 Mar;71(3):315-326. ASERTAA Trial - Pharmacogenetic Study of IR Vs. Extended-Release Tacrolimus in African American Kidney Transplant Recipients • • Observed mean tacrolimus whole blood time-concentration curves by CYP3A5 expresser status for Envarsus®. No significant difference in the AUC and Cmax. Trofe-Clark J et al. Results of ASERTAA, a Randomized Prospective Crossover Pharmacogenetic Study of Immediate-Release Versus Extended-Release Tacrolimus in African American Kidney Transplant Recipients. Am J Kidney Dis. 2018 Mar;71(3):315-326. Drug-Drug Interactions Drug-Drug Interactions • Coadministration of tacrolimus with cyclosporine results in additive or synergistic nephrotoxicity; therefore, a delay of at least 24 h is required when switching a patient from cyclosporine to tacrolimus. • Any drug that affects CYP3A4/5, may affect cyclosporine, tacrolimus, sirolimus and everolimus blood concentrations. • Substances that inhibit CYP3A4/5 can decrease metabolism and increase blood concentrations. • Grapefruit juice inhibits CYP3A4/5 and the Pglycoprotein multidrug efflux pump and thereby can increase concentrations. • In contrast, drugs that induce CYP3A activity can Krensky AM, Azzi JR, Hafler DA. Immunosuppressants and Tolerogens. In: Brunton LL, Hilal-Dandan R, Knollmann BC. eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e New York, NY: McGraw-Hill. Effect of Concomitant Drug Administration on Cyclosporine, Tacrolimus, Sirolimus, and Everolimus Cyclosporine Levels Increase Ketoconazole Fluconazole Itraconazole Voriconazole Erythromycin Levofloxacin Diltiazem Verapamil Nicardipine Decrease Tacrolimus Levels Increase Rifampicin Ketoconazol e Carbamazepi Fluconazole ne Itraconazole Phenytoin Voriconazol Phenobarbita e l Clotrimazol e Trimethoprim Erythromyci Mycophenolic n Acid (vs. TAC) Levofloxacin Decrease Sirolimus and Everolimus Levels Increase Decrease Rifampin Ketoconazole Fluconazole Dexamethason Itraconazole e Voriconazole Phenytoin Rifampin Phenytoin Erythromycin Clarithromycin Diltiazem Verapamil Atorvastatin Cyclosporine Metoclopramide Diltiazem Verapamil Norethisterone Omeprazole Sirolimus Tacrolimus Protease inhibitors (HIV and HCV) Protease inhibitors (HIV and HCV) Nefazodone Cyclosporin e Basiliximab Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Drug-Drug Interactions • Interactions between CNIs and sirolimus require that administration of the two drugs be separated by time. • Sirolimus aggravates CNI-induced renal dysfunction, while CNIs increases sirolimus-induced hyperlipidemia and myelosuppression. • Additive nephrotoxicity may occur when CNIs are coadministered with NSAIDs and other drugs that cause renal dysfunction • Elevation of methotrexate levels may occur when CNIs are co-administered, as can reduced clearance of other drugs, including prednisolone, digoxin, and statins. Krensky AM, Azzi JR, Hafler DA. Immunosuppressants and Tolerogens. In: Brunton LL, Hilal-Dandan R, Knollmann BC. eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e New York, NY: McGraw-Hill. Cyclosporine and Ketoconazole Interaction • Some have taken advantage of these interactions by routinely prescribing CYP3A4 inhibitors to reduce the dosage and cost of CNI therapy while maintaining the same therapeutic concentrations. • Coadministration of cyclosporine and ketoconazole results in marked elevation in blood levels of cyclosporine. • This requires a significant reduction in cyclosporine dosage regimen which may result in savings of nearly Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. $5,000/year per transplant Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. https://www.nejm.org/doi/full/10.1056/NEJM199509073331004 recipient. Drug-Drug Interactions • All of the following reduce the Cellcept® and Myfortic® blood levels significantly • Antacids (Magnesium and Aluminum Hydroxides) – Separate doses by at least 2 hours • Cholestyramine – Avoid combination • Calcium Polycarbophil (e.g. Fibercon) – Avoid combination Azathioprine • Xanthine oxidase, an enzyme of major importance in the metabolism of azathioprine metabolites, is blocked by allopurinol. • Hence, the combination of azathioprine with allopurinol should be avoided. • Adverse effects resulting from coadministration of azathioprine with other myelosuppressive agents or angiotensin-converting enzyme inhibitors include leukopenia, thrombocytopenia, and anemia as a result of myelosuppression. Krensky AM, Azzi JR, Hafler DA. Immunosuppressants and Tolerogens. In: Brunton LL, Hilal-Dandan R, Knollmann BC. eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e New York, NY: McGraw-Hill. https://www.ebmconsult.com/articles/allopurinol-azathioprine-interaction- Prednisone • Barbiturates, phenytoin, and rifampin induce hepatic metabolism of prednisone and thus decrease the effectiveness of prednisone. • Prednisone decreases the effectiveness of vaccines and toxoids. Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Question s • Please contact me at: [email protected] u