Renal Impairment From Dettli to Guideline: What can we learn?

Transcription

1 Renal Impairment From Dettli to Guideline: What can we learn? SocraMetrics GmbH Mainzerhofplatz Erfurt phone: fax: SocraMetrics GmbH Page 1/33

2 program The concept of Dettli for dose adjustment in renally impaired patients Critical Points of Dettli s concept Answers given by the current European guideline What can we learn? SocraMetrics GmbH Page 2/33

3 The concept of Dettli 1.00 Q drug elimination renal atenolol Q 0 = 0.06 cephalexin Q 0 = 0.03 gentamicin Q 0 = extrarenal phenprocoumon Q 0 = 1.00 diazepam Q 0 = Q 0 loratadine Q 0 = 1.00 extrarenally eliminated drug Q 0 t 1/2 (healthy) fractions of drugs in healthy subjects are tabulated SocraMetrics GmbH Page 3/33

4 The concept of Dettli 1.00 Q Q 0 = 0.06 Q GFR (Glomerular Filtration Rate) creatinine clearance [ml/min] 1 st example: atenolol 2 nd example: pravastatin 0.00 Q 0 = 0.5 SocraMetrics GmbH Page 4/33

5 The concept of Dettli 1.00 Q Q 0 = 0.06 Q GFR (Glomerular Filtration Rate) creatinine clearance [ml/min] 1 st example: atenolol 2 nd example: pravastatin 0.00 Q 0 = 0.5 SocraMetrics GmbH Page 5/33

6 The concept of Dettli 1 st example: atenolol: t 1/2 c c single dose multiple dose dose adjustment required SocraMetrics GmbH Page 6/33

7 The concept of Dettli 1. step: find the individual elimination Q Q 0 Table drug Q 0 t 1/2 (healthy) GFR individual measurement in patient individual elimination Q = Q 0 + ( 1- Q 0 )x GFR 100 [ml/min] SocraMetrics GmbH Page 7/33

8 The concept of Dettli Example atenolol atenolol : Q 0 = 0.06 individual GFR of patient : CL cr : 40 ml/min individual elimination Q = Q 0 + ( 1- Q 0 )x GFR 100 [ml/min] atenolol: Q = (1-0.06) x 40/100 =0.44 SocraMetrics GmbH Page 8/33

9 The concept of Dettli 1.0 Q 0 + ( 1- Q 0 )x GFR 100 [ml/min] 0.8 individual elimination [Q] Q = 0.44 Q = Q = creatinine clearance [ml/min] linear relation SocraMetrics GmbH Page 9/33

10 The concept of Dettli 2. step: apply one of Dettli s rules for dose adjustment rule 1: dose (healthy) x Q = individual dose D x Q = D i 25 mg x 0.44 = 11 mg rule 2: dose interval (healthy) Q τ τ / Q = i 24 h / h = individual dose interval. or combine rule 1 and rule 2 SocraMetrics GmbH Page 10/33

11 The concept of Dettli 2 nd example: pravastatin Q 0 = 0.50 pravastatin serum concentration [ng/ml] healthy GFR < 30 ml/min 5 time [h] Halstenson et al., J Clin Pharmacol 1992 SocraMetrics GmbH Page 11/33

12 The concept of Dettli 2 nd example: pravastatin Q 0 = 0.50 pravastatin serum concentration [ng/ml] healthy GFR < 30 ml/min 5 time [h] Halstenson et al., J Clin Pharmacol 1992 SocraMetrics GmbH Page 12/33

13 The concept of Dettli healthy GFR < 30 ml/min C max [ng/ml] AUC [hng/ml] t 1/2 [h] Cl R [L/h] Cl H [L/h] escape pathway SocraMetrics GmbH Page 13/33

14 The concept of Dettli GFR (Glomerular Filtration Rate) creatinine clearance [ml/min] c c SocraMetrics GmbH Page 14/33

15 Summary Critical Points when using Dettli s dose adjustment rely on Q 0 and t 1/2 data of healthy subject Are we really sure the relations are not changed in impaired subjects? rely on linear relations How can we know? course of plasma concentration data not known Course in patient possibly altered? Do we have particularities in impaired subjects? We simply don t know! SocraMetrics GmbH Page 15/33

16 Summary Dettli Guideline Two different worlds dose recommendations for the individual patient dose recommendations for clinician via SPC clinical investigation SocraMetrics GmbH Page 16/33

17 Summary Dettli Guideline Concludes from healthy subjects to patients Guideline should claim investigations in patients Information of individual elimination features Guideline should allow predictions for a range of representative patients Classification / matching of patients needed Single point estimation of individual GFR Classification / Grouping of GFR needed SocraMetrics GmbH Page 17/33

18 Summary Dettli No information of plasma concentration course Curves needed elimination characteristics rate and extent of exposure particularities No hints on exact renal / extrarenal fractions eliminated in the patient Guideline should claim correlations No hints on particularities in patients Guideline should claim data description (exceptional results / particularities) Guideline SocraMetrics GmbH Page 18/33

19 Note for Guidance on the evaluation of the pharmacokinetics of medicinal products in patients with impaired renal function Date of coming into operation: December 2004 SocraMetrics GmbH Page 19/33

20 Objectives of the current Guideline Situations where studies of pharmacokinetics are needed Design and conduct of pharmacokinetic studies Data analysis, presentation and evaluation of results Reflection of results in the SPC Does the guideline answer the claims we have? SocraMetrics GmbH Page 20/33

21 Guideline should claim investigations in patients Study population investigation in patients with the condition for which the drug is intended alternative is to use volunteers with different degree of renal function SocraMetrics GmbH Page 21/33

22 Guideline should allow predictions for a range of representative patients Classification / matching of patients needed The renal function groups should be comparable with respect to factors, which are expected to significantly influence the pharmacokinetics of the drug. these may be demographic factors such as age, gender or weight or other factors SocraMetrics GmbH Page 22/33

23 Classification / Grouping of GFR needed Group Description GFR (ml/min/1.73m²) 1 Normal renal function >80 2 Mild renal impairment Moderate renal impairment 30 - <50 4 Severe renal impairment <30 5 End stage renal disease (ESRD) Requiring dialysis marker substances exogenic 51Cr-EDTA 99mTc-DTPA Iothalamate Iohexol endogenic Creatinine Cystacin C exact method of determination not defined! SocraMetrics GmbH Page 23/33

24 Full approach Group Description GFR (ml/min/1.73m²) 1 Normal renal function >80 2 Mild renal impairment Moderate renal impairment 30 - <50 4 Severe renal impairment <30 5 End stage renal disease (ESRD) Requiring dialysis Only when linear PK relations may be assumed SocraMetrics GmbH Page 24/33

25 Full Reduced/staged approach design Group Description GFR (ml/min/1.73m²) 1 Normal renal function >80 2 Mild renal impairment Moderate renal impairment 30 - <50 4 Severe renal impairment <30 5 End stage renal disease (ESRD) Requiring dialysis first step: extremes second step: intermediate groups if the applicant wants to confirm that the pharmacokinetics is not altered to a clinically relevant extent SocraMetrics GmbH Page 25/33

26 Curves needed elimination characteristics rate and extent of exposure particularities Plasma concentration data (and urinary excretion data if collected) should be analysed. Parent compound & pharmacologically active / toxicologically relevant metabolites AUC, C max, t 1/2, Cl/F multiple dose design urinary excretion data C min, PTF and trough values Cl R SocraMetrics GmbH Page 26/33

27 Guideline should claim correlations Guideline should claim data description Data should be presented in several ways: Graphical description of the relationship between renal function and pharmacokinetics Modelling of the relationship between renal function and pharmacokinetics Descriptive statistics of the pharmacokinetic parameters according to renal function group SocraMetrics GmbH Page 27/33

28 The graphical presentation should describe the relationship between individual pharmacokinetic parameters and renal function correlations drug clearance AUC C max drug clearance AUC C max GFR GFR GFR plasma albumin plasma albumin plasma albumin drug clearance [ml/min] correlation analysis severe moderate mild healthy creatinine clearance [ml/min] SocraMetrics GmbH Page 28/33

29 plasma concentration healthy severe possible alterations in course of the curve time [h] alteration of absorption phase due to concomitant liver disease plasma concentration time [h] SocraMetrics GmbH Page 29/33

30 What can we learn? the principles of Dettli bear some critical points to be handled with care Clinicians should more rely on advices for dose adjustments given in the Summary of Product Characteristics (SPC) if applicable SocraMetrics GmbH Page 30/33

31 However,. What can we learn? it s not all about pharmacokinetics! - pharmacokinetic/pharmacodynamic relations - possible concomitant medications - possible concomitant diseases - The clinician needs to justify a dose adjustment keeping in mind all of these aspects! Is there any way out? SocraMetrics GmbH Page 31/33

32 What can we learn? Alternatives mentioned in the guideline: Population pharmacokinetics Evaluations of patients participating in phase II/phase III clinical trials can be used in case a PK-study in patients has been conducted prior to phase III, a subsequent population analysis can be used to confirm the results. if it s pre-planned and includes a sufficient number of patients, a Population PK-study can be an acceptable alternative SocraMetrics GmbH Page 32/33

33 What can we learn? Alternatives mentioned in the guideline: Pharmacodynamic assessments information regarding the PK/PD relationship in renal impairment inclusion of e.g. relevant biomarkers for efficacy and safety Thank you for your attention! SocraMetrics GmbH Page 33/33