1. cpms predict and confirm Prediction of clinically active doses of anticancer candidates based on preclinical data Monica Simeoni & Italo Poggesi 9 th December 2008 Monica Simeoni PAGE, 23 rd June 2009 Defining clinical relevance: model-based update of the label

2. cpms predict and confirm Remifentanil hydrochloride (ULTIVA™) selective  -opioid receptor agonist for injection during the induction and maintenance of general anaesthesia. has a short effective biological half-life of less than 10 minutes. administered for long periods of time and at high doses without risk of significant accumulation. Intensive care unit (ICU) subjects have varying degrees of organ dysfunction, so the organ independent metabolism of remifentanil makes it a very useful agent in this setting metabolised to remifentanil acid (RA) which has been shown to be 1/4600 times less potent than remifentanil. RA is therefore thought not to result in any clinically relevant effects at concentrations below 900 ng/ml. Remifentanil acid is eliminated via the kidney and in subjects with severe renal impairment its elimination is prolonged.

3. cpms predict and confirm The label The current GDS statement quotes: “The clearance of the carboxylic acid metabolite is reduced in patients with renal impairment. In intensive care patients with moderate/severe renal impairment, the concentration of the carboxylic acid metabolite is expected to reach approximately 100 fold the level of remifentanil at steady-state.”

4. cpms predict and confirm Issue This statement follows the analysis of a up to 3 day treatment study (3d study) where the concentrations did not reach the steady state (SS) and the metabolic ratio (MR) defined as: MR=(Conc metabolite /Conc parent ) SS was approximated as: MR  AUC_last metabolite /AUC_last parent Questions:  can we have a more precise measurement of MR in non-steady state conditions?  after an up-to 10 days treatment study (10d study), is this statement still valid?

5. cpms predict and confirm Data Both studies contained subjects with normal renal function and subjects with mild, moderate and severe renal impairment. Arterial remifentanil and remifentanil acid concentrations in the 10d study were very limited, given they were based on a particularly sparse sampling regimen, while concentration-time data from the 3d study were more extensive, following a serial sampling regimen

6. cpms predict and confirm Data Subj from 10d study. Sparse sampling (N=53, samples=198) The system was not in steady state conditions. The infusion rate is rapidly varying within the study time interval. In 3d study each subject received a different infusion rate in order to maintain a Sedation-Agitation Scale (SAS) score 2-4 with no, or only mild pain. Subj from 3d study. Extensive sampling (N=40, samples=1689)

7. cpms predict and confirm Data moderate / severe renal impairment normal / mild renal impairment Pitsiu et al., British Journal of Anesthesia, 2004

8. cpms predict and confirm Two-compartment model: moderate / severe renal impairment Three-compartment model: normal / mild renal impairment where R= remifentanil, M metabolite The original Model

9. cpms predict and confirm In our analysis the clearance of metabolite has been modelled as a function of creatinine clearance (CRCL) and the regression parameters directly estimated from the overall model: At steady state the ratio of the metabolite versus the parent (metabolic ratio) was calculated in Pitsiu et al as the ratio of their AUC last. In our analysis the metabolic ratio is calculated from the general model at steady state and is equal to the ratio of the inverse of the two clearances: The Model: novel parameter description

10. cpms predict and confirm Methods Pitsiu et al were limited to modelling the concentration data for each individual separately Non-Linear Mixed-Effect approach was employed in the current analysis and an update of the structural model presented by Pitsui et al. was implemented Population analysis of the combined dataset was not successful likely for the heterogeneity of the two. Population analysis of 3d study and with the estimated parameters posthoc analysis (MAXEVAL=0) of 3d and 10d studies

11. cpms predict and confirm Methods Model validation: given the different infusion profile for each subject it was not possible to perform the standard visual predictive check (VPC) considering all the subjects together, instead the VPC of 300 simulated parent and metabolite profiles for each subject and the VPC of the corresponding 300 estimates of the metabolic ratio for each subject were performed

12. cpms predict and confirm Results: VPC

13. cpms predict and confirm Results: PPC Moderate/severe renal impaired subjectsnormal, mild renal impaired subjects

14. cpms predict and confirm Results: posthoc analysis 3d Study 10d Study

15. cpms predict and confirm Results: posthoc analysis parent metabolite Open circles = 3d study, red circles = 10d study (ng/ml)

16. cpms predict and confirm Normal/Mild (N=51)Moderate/Severe (N=42) Remifentanil CL (mL/h/kg) Remifentanil Acid CL (mL/h/kg) MR Remifentanil CL (mL/h/kg) Remifentanil Acid CL (mL/h/kg) MR 2900 (681- 13785) 233 (5.09 - 11753) 12.46 (0.23 - 243) 3019 (1607 - 10859) 42.8 (7.34 - 464) 70.6 (5.86 - 352) Normal/Mild (N=12)Moderate/Severe (N=28) Remifentanil CL (mL/h/kg) Remifentanil Acid CL (mL/h/kg) MR Remifentanil CL (mL/h/kg) Remifentanil Acid CL (mL/h/kg) MR 2650 (1231 – 10013) 169.6 (113 – 270) 15.6 (7.50 – 41.5) 2743 (1607 – 10885) 36.3 (7.34 – 151) 75.6 (19.5 – 352) Summary (geometric mean & range) of individual predictions of remifentanil and remifentanil acid clearance along with predicted MR in 3d study Summary (geometric mean & range) of individual predictions of remifentanil and remifentanil acid clearance along with predicted MR in combine dataset of 3d and 10d study Results: posthoc analysis

17. cpms predict and confirm Predicted typical and individual values of remifentanil acid clearance (CLM) (left, upper panel) and metabolic ratio (MR) (left, lower panel); p values (i.e. 1-cpf) of the lognormal distributions of MR in the typical subject of group 1 and group 2 (right panel). Results: MR estimate from the mixed effect model

18. cpms predict and confirm Conclusions The model-based approach allowed us to estimate the MR, defined as a steady state parameter, in non-steady state conditions MR was estimated to exceed 200 in approximately 12% of ICU patients with moderate/severe renal impairment. Following this findings, the label is in the process to be updated. The current proposed text is: “The clearance of the carboxylic acid metabolite is reduced in patients with renal impairment. In intensive care patients with moderate/severe renal impairment, the mean concentration of the carboxylic acid metabolite is not expected to exceed 100 fold the level of remifentanil at steady-state.... ”

19. cpms predict and confirm Acknowledgments Chao Chen and Jonathan Bullman Remifentanil project team

20. cpms predict and confirm Back-up

21. cpms predict and confirm Studies-USA30212 & USA30226 USA30212 was an open label, non-comparator multi-centre study to assess the safety, efficacy and pharmacokinetics of Remifentanil in intensive care unit patients with varying degrees of renal dysfunction requiring analgesia and sedation in association with mechanical ventilation. Study treatment was permanently discontinued after a maximum of 72h, by reducing the Remifentanil infusion rate by 25% at 10 min intervals. Remifentanil and remifentanil acid concentrations were determined following extensive blood sampling study USA30212 USA30226 was a randomised, open-label, multicentre, parallel group study comparing the safety and efficacy of an ULTIVA™ (Remifentanil Hydrochloride) based analgesia/sedation regimen with a conventional sedative based regimen in long-term ICU subjects requiring analgesia and sedation for up to 10 days. Remifentanil and remifentanil acid concentrations were determined following sparse sampling in study USA30226.

22. cpms predict and confirm Back-up

23. cpms predict and confirm THETA/Parameter/UnitsEstimate Precision of the Estimate (%)  1, V1 (Remifentanil), L/kg 0.51315.1  2, CL (Remifentanil), mL/min/kg 45.58.3  3, A (see Equation. 3) (Remifentanil Acid), mL/h/kg 25.314.4  4, V2 (Remifentanil Acid), L/kg 0.774.6  5, V3 (Remifentanil Acid), L/kg 0.37827.2  6, Q (Remifentanil Acid), mL/h/kg 30.631.2  7, B (see Equation. 3) (Remifentanil Acid), mL/h/kg 2.410.5 IIV, V1, %CV 66.046.7 IIV, CL, %CV 48.334.0 IIV, CLM, %CV 47.927.5 IIV, V2, %CV 30.726.3 RUV, proportional, %CV (Remifentanil) 21.733.7 RUV, proportional, %CV (Remifentanil Acid) 18.820.4 RUV, additive, SD, ng/mL (Remifentanil) 0.4535.0 RUV, additive, SD, ng/mL (Remifentanil Acid) 0.6150.1 Summary of estimates of population pharmacokinetic parameters and associated variability from study USA30212 Results

24. cpms predict and confirm Ultiva renewal is needed for Mexico. Ultiva FREP is for Peru, Nigeria, Albania, & Malaysia. Europe is also in progress