Update on DDI Guidance of the FDA - In Vitro

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1 Update on DDI Guidance of the FDA - In Vitro Xinning Yang, Ph.D. Policy lead Guidance & Policy Team (GPT) Office of Clinical Pharmacology (OCP) Office of Translational Sciences (OTS) Center for Drug Evaluation and Research (CDER), FDA

2 DDI with CYP enzymes NME as a substrate NME as an inhibitor NME as an inducer DDI with transporters NME as a substrate NME as an inhibitor Outline Case example 2

3 In vitro guidance In Vitro In Vivo Define potential for drug interactions of an investigational drug Metabolic enzymes CYP isoforms Transporters Help determine what in vivo interaction studies are needed 3

4 In Vitro evaluation- CYP enzymes CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6*, 3A4/5 Evaluate an NME as a substrate - routine If 25% clearance by an enzyme (in vitro phenotyping; human PK), need further clinical evaluation, i.e., evaluate effect of inhibitor and inducer of the enzyme on the PK of the NME Evaluate an NME as a perpetrator (inhibitor and/or inducer) - routine Apply equations with cut-off values to determine whether in vivo studies are needed *CYP2D6 is not inducible by drugs, though its activity is increased in pregnancy women. 4

5 Determine whether drug is an inhibitor of CYP enzymes- Basic model If the R value is above the cut-off, further evaluation of the DDI potential is needed. - Reversible inhibition R 1 = 1 + (I max,u / K i ) 1.02 R 1,gut = 1 + (I gut / K i ) 11 I max : steady-state C max of the inhibitor in plasma; u means unbound (free) drug (Imax,u = Imax x fu,p); Ki is unbound inhibition constant determined in vitro For CYP3A, R 1,gut should also be calculated; I gut : Dose/250mL (a rough estimate of intestinal luminal concentration of inhibitor. - Time-dependent inhibition (TDI) R 2 = (k obs + k deg ) / k deg 1.25 Where k obs = (k inact 50 I max,u ) / (K I + 50 I max,u ) 5

6 Updates from 2012 FDA Guidance Inhibitor concentration for R 1 (reversible) and R 2 (TDI): total (unbound + plasma protein bound) unbound (same as EMA DDI guideline) Threshold for R 1 : Imax/Ki 0.1 Imax,u/Ki 0.02 (same as EMA) Imax,u/Ki 0.02 is equal to R TDI: Multiple a factor of 50 for Imax,u (same as EMA) TDI: no need to calculate ratio using Igut. (different from EMA) Rationale for the change? Our recent analysis (see Table 3 in the reference) suggests these criteria performed similarly in predicting positive DDIs mediated by CYP3A inhibition, e.g. sensitivity, specificity, positive predictive value, negative predictive value, fold error 6 Viera ML, et al. Clin Pharmacol Ther 95(2): (2014).

7 Determine if NME is an Inducer of CYP enzymes Evaluate CYP1A2, CYP2B6, and CYP3A4/5 initially. If no induction of CYP3A4/5 is observed, evaluating the induction potential of CYP2C enzymes is not necessary because both CYP3A4/5 and CYP2C enzymes are induced via activation of the pregnane X receptor (PXR). If the drug induces CYP3A4/5, evaluate the drug s potential to induce CYP2C enzymes. P-gp and certain Phase II enzymes (e.g., UGT) may be coinduced with CYP3A. Modified from Lei Zhang 7

8 Evaluate Induction Potential Fold-change method Examine the fold-change in CYP enzyme mrna levels when incubated with the investigational drug Use a cutoff determined from known positive and negative controls to calibrate the system. (e.g., a 2-fold increase in mrna and a response 20% of the response of the positive control) Correlation method Predicted positive criteria defined by known positive (e.g., known inducers of the same enzyme) and negative controls (e.g., relative induction score (RIS)) Basic kinetic model R 3 = 1 / [1 + (d Emax 10 Imax,u) / (EC Imax,u)] 0.8 (compared to 2012 guidance, Imax 10 x Imax,u; the cut-off changed from ) Compared to the 2012 guidance, correlation method was mentioned and activity measurement was added back (besides mrna). Yoshida K, et al. J Pharm Sci Sep;106(9): Modified from Lei Zhang 8

9 Determine if NME is an Inhibitor or Inducer of Metabolizing Enzymes CYP inhibitor (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A) CYP inducer (CYP1A2, 2B6, 2C8, 2C9, 2C19, 3A) Determine in vitro parameters Basic Model Mechanistic, static Mechanistic, dynamic (e.g., PBPK) In vivo DDI study From Lei Zhang 9

10 Transporter-Mediated Drug Interactions Determine if NME is a substrate of transporters Determine if NME is an inhibitor of transporters * Current knowledge about transporter induction is quite limited; consider evaluating P-gp induction if CYP3A induction is observed. 10

11 Investigational Drug as a Substrate of Transporters P-gp and BCRP (efflux transporters, in intestine, liver, kidney, blood-brain barrier, etc.) Intestinal absorption is likely to be a major cause of the variability in drug PK and response. The drug needs be transported into certain tissues to exert a pharmacological effect (e.g., brain) OATP1B1 and OATP1B3 (hepatic uptake transporters) Hepatic/biliary elimination is significant Physiological properties (e.g., anion at physiological ph, high hepatic concentrations relative to other tissues, low passive permeability) OAT1, OAT3, OCT2, MATE1, MATE2/K (renal uptake or efflux transporters) Signiant active renal secretion ( 25% of systemic clearance of the drug) or concerns about renal toxicity If a drug is a transporter substrate, the need for clinical DDI studies is determined by: drug s putative site of action, route of elimination, likely concomitant drugs, and safety considerations. 11

12 Investigational Drug as an Inhibitor of Transporters Does the drug affect a given transporter? Evaluate an NME as an inhibitor for P-gp, BCRP; OATP1B1, OATP1B3; OAT1, OAT3, OCT2, MATE1, MATE-2K Applicable for most drugs (a drug not as a substrate of a transporter doesn t mean it cannot be an inhibitor) Basic Models for predicting in vivo inhibition potential of transporters by the NME Is relevant inhibitor concentrations [I]/IC 50 cutoff value? If yes, inhibition is possible. Induction? - in vitro methods are not well established P-gp is also regulated by PXR, but less sensitive than CYP3A. Modified from Lei Zhang 12

13 Decision for In Vivo Study mediated by Transporter Inhibition Transporters 2012 Draft guidance 2017 Draft Guidance P-gp I 1 /IC or I 2 /IC I 2 /IC (for oral drugs) OATP1B1/ OATP1B3 Step 1: I total, max /IC Step 2: I unbound, inlet, max /IC I unbound, inlet, max /IC OAT1/OAT3 I unbound, max /IC Remained the same OCT2/MATE1/ MATE2-K I unbound, max /IC (only for OCT2) I u, max /IC for OCT2 OR I u, max /IC for MATEs If the ratio is above the cut-off, the sponsor should further investigate the DDI potential by either using mechanistic static models or PBPK or conducting a clinical DDI study. 13

14 P-gp: Comparison of Prediction Performance with Different Cut-off Criteria EMA 1 PMDA& FDA 2 I 2 /IC 50 alone (#1) I 1u /IC OR I 2 /IC I 1 /IC OR I 2 /IC I 2 /IC I 2 /IC 50 alone (#2) I 2 /IC FN (#) 6 (11%) 6 (11%) 6 (11%) 8 (15%) FP (#) 12 (23%) 12 (23%) 11 (21%) 7 (13%) TN (#) 16 (30%) 16 (30%) 17 (32%) 21 (40%) TP (#) 19 (36%) 19 (36%) 19 (36%) 17 (32%) PPV 61% 61% 63% 71% NPV 73% 73% 74% 72% I 2 /IC alone (I 2 = Dose/250 ml, reflecting inhibitor concentration in intestine) seems sufficient for reasonable prediction of P-gp mediated DDIs for oral drugs. For drugs given parentally or metabolite that are the inhibitors, a different cut-off with systemic concentrations (e.g., Imax or Imax,u) will be more appropriate and needs further evaluation EMA DDI guideline PMDA draft DDI guideline and 2012 FDA draft DDI guidance. 3 Lee SC, et al., Adv Drug Deliv Rev Jul 1;116:

15 Case Example - Dolutegravir Dolutegravir is an orally administered anti-hiv drug. Cmax of dolutegravir was 4.1 μg/ml at 50 mg b.i.d. It is highly bound ( 98.9%) to human plasma proteins. An in vitro experiment was conducted to measure the uptake of metformin (OCT2 substrate) with the absence or presence of dolutegravir, generating an IC 50 value of dolutegravir as 1.93 μm (or 0.81 μg/ml). Is there a potential for dolutegravir to inhibit OCT2 in vivo and cause clinically significant drug interactions? Is there a need to further conduct an in vivo DDI study with OCT2 substrate(s)? 15

16 Case Example - Dolutegravir Cmax,u/IC 50 = 0.05 < 0.1 thus, it would be concluded that dolutegravir won t cause clinically relevant DDIs mediated by inhibition of OCT2 in humans. No further DDI assessment is needed. There is fold difference in IC 50 of dolutegravir against OCT2, i.e., 0.11 μm (or μg/ml) using metformin as the substrate. This was confirmed by another source reporting an IC 50 of 0.21 μm. Using the new data, Cmax,u/IC50 = 0.89 > 0.1, it would be concluded that dolutegravir may cause clinically relevant DDI. Lepist EI, Kidney Int. Kidney Int Aug; 86(2): Chu X, et al. Drug Metab Dispos Sep;44(9):

17 Dolutegravir Metformin DDI Dolutegravir USPI: With concomitant use, limit the total daily dose of metformin to 1,000 mg either when starting metformin or TIVICAY. When stopping TIVICAY, the metformin dose may require an adjustment. Monitoring of blood glucose when initiating concomitant use and after withdrawal of TIVICAY is recommended. Also contraindicate with dofetilide, an OCT2 substrate, considered as a narrow therapeutic index drug Song IH, et. al. J Acquir Immune Defic Syndr Aug 1;72(4):

18 Why there was discrepancy in the in vitro data? Dr. Yong Huang, Optivia Biotechnology Inc. April

19 Conclusions In Vitro experiment results inform in vivo DDI evaluation strategy (the need, the timing, etc.). An integrated approach can be used to leverage available in vitro/in vivo information to evaluate DDI potential (e.g., simple model, mechanistic static and/or dynamic model). The criteria of simple models (the matrix, the cut-off values) will be continuously evaluated for their prediction performance with more data becoming available and may be updated. Standardize and validate in vitro assay conditions to ensure data with good quality (e.g., including proper controls, check recovery/mass balance, pay attention to potential non-specific binding) 19

20 Acknowledgements Kellie Reynolds Lei Zhang Shiew-Mei Huang Joseph Grillo Ping Zhao* Darrell Abernethy Issam Zineh Jayabharathi Vaidyanathan Arya Vikram Zhongqi Dong* Tian Zhou Dinko Rekic* Kenta Yoshida* *former FDA colleagues 20

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22 OATP1B1: Comparison of Prediction Performance with Different Cutoff Criteria Method 1: I max /K i 0.1 2: I u,max /K i : R 1.04 (EMA) 4: R 1.1 5: R 1.25 (PMDA) 6: I max /K i 0.1 and R 1.25 (FDA 2-step) FN 12 (11%) 17 (16%) 8 (7%) 12 (11%) 15 (14%) 17 (16%) FP 27 (25%) 16 (15%) 33 (31%) 22 (21%) 16 (15%) 13 (12%) TN 28 (26%) 39 (36%) 22 (21%) 33 (31%) 39 (36%) 42 (39%) TP 40 (37%) 35 (33%) 44 (41%) 40 (37%) 37 (35%) 35 (33%) PPV 60% 69% 57% 65% 70% 73% NPV 70% 70% 73% 73% 72% 71% R 1.1 (Iu,inlet,max/IC , unbound liver inlet concentrations of inhibitor) seems providing a better balance between false negative and false positive predictions. Lee SC, et al., Adv Drug Deliv Rev Jul 1;116:

23 OAT1/OAT3: Comparison of Prediction Performance with Different Cut-off Criteria C max,u / IC 50 EMA 0.02 a All substrates (59 DDI Studies) OAT1-specific substrates (13 DDI Studies) OAT3-specific substrate (32 DDI Studies) FDA PMDA EMA FDA PMDA EMA FDA PMDA 0.1 b 0.25 c 0.02 a 0.1 b 0.25 c 0.02 a 0.1 b 0.25 c FN 0 1 d 1 d d 1 d FP TP TN PPV 52% 64% 72% 60% 86% 86% 43% 50% 60% NPV 100% 96% 97% 100% 100% 100% 100% 93% 94% The cut-off value 0.02 (EMA) yielded more false positives. The value 0.1 (FDA) or even 0.25 (PMDA) seems to be a reasonable cut-off. Lee SC, et al., Adv Drug Deliv Rev Jul 1;116:

24 OCT2/MATEs: Comparison of prediction performance of different cut-off criteria EMA a ITC b PMDA c #4 #5 #6 #7 #8 #9 C max,u / IC 50 OCT OR MATEs 0.02 OCT2 0.1 OR MATEs 0.1 OCT OR MATEs 0.25 OCT OR MATEs 0.1 MATEs 0.25 MATEs 0.02 OCT2 0.1 OR MATEs 0.25 MATEs 0.02 OCT OR MATEs 0.1 FN 0 2 d 3 d d 0 3 d FP TP TN PPV NPV 64% 64% 75% 64% 64% 64% 73% 67% 65% 100% 75% 77% 100% 100% 100% 82% 100% 70% a A cut-off of 0.02 applied to unbound C max /IC 50 for OCT2 or for MATEs was suggested in 2012 EMA DDI guideline; b A cut-off of 0.1 for OCT2 or for MATEs was suggested in ITC paper (Hillgren KM, et. al, Clin Pharm Ther, 94(1):52-63, 2013). As of note, 2012 FDA s draft DDI guidance has a cutoff of 0.1 only for OCT2; c A cut-off of 0.25 was suggested in 2014 PMDA draft DDI guideline. d Among these false negatives, two DDI records were between ranolazine (inhibitor, different doses) and metformin (substrate) (Zack J, Clin Pharm in Drug Develop, 4(2) , 2015). The other DDI study was between isavuconazole and metformin (Clinical Pharmacology and Biopharmaceutical review for NDA from Drugs@FDA). Z. Dong, X. Yang, V. Arya, L. Zhang, CPT, 2016, Vol. 99, Issue Supplement S1, S From Lei Zhang