# Presentation: 705893

## Concentration-Controlled Trials and Therapeutic Drug Monitoring

- TM

***RAPAMUNE******®***

**Concentration-Controlled Trials and Therapeutic Drug Monitoring**

**James Zimmerman,  PhD**
**Senior Director, Clinical Pharmacokinetics****Clinical Research and Development****Wyeth-Ayerst Research**

## Key Messages in This Presentation

**There is sufficient understanding of sirolimus PK to apply therapeutic drug monitoring (TDM) in patients**
**A robust and reliable sirolimus assay is available**
**The concentration range for sirolimus TDM has been defined and is effective **
**Data are available to show that physicians can use TDM in renal allograft patients**

## The currently approved RAPAMUNE regimen is a fixed-dose regimen (RAPA administered 4 hours after cyclosporine)
Fixed-dose administration is recommended for most patients during  co-administration with cyclosporine

**Fixed-dose administration is recommended for most patients during  co-administration **_**with**_** cyclosporine**

**Currently Approved****RAPAMUNE Regimen **

## Recommended when administered with cyclosporine (RAPA administered 4 hours after cyclosporine)
in pediatric patients
in hepatic impairment
during administration with strong inducers/inhibitors of CYP3A and P-gp
after marked changes in cyclosporine doses
Required when administered without cyclosporine
Method of dose administration for the proposed indication (RAPA administered 4 hours after cyclosporine)

**in pediatric patients**
**in hepatic impairment**
**during administration with strong inducers/inhibitors of CYP3A and P-gp**
**after marked changes in cyclosporine doses**
_**Required**_** when administered **_**without cyclosporine**_
**Method of dose administration for the proposed indication (RAPA administered 4 hours after cyclosporine)**

**Concentration-Controlled****RAPAMUNE Administration**

## Two Sirolimus Assay Methods Were Used to Measure Trough Levels

**Two Sirolimus Assay Methods Were Used to Measure Trough Levels**

** ****Sirolimus concentrations in this presentation**
**are expressed in terms of the immunoassay**

## Sirolimus Dose-Proportionality and aLinear Cmin vs AUC Relationship Simplify Concentration- Controlled Dosing 

## The Sirolimus Cmin vs AUC Relationship is Linear (Study 301, RAPA + Cyclosporine)

## Sirolimus Pharmacokinetics Influences the Implementation of Concentration-Controlled Dosing 

**Sirolimus Pharmacokinetics**** Influences the Implementation of Concentration-Controlled Dosing **

## Four Studies Contributed Data for RAPAMUNE Concentration-Controlled Regimens

**Four Studies Contributed Data for RAPAMUNE Concentration-Controlled Regimens**

**Time**

**Post-transplant**

**Studies**

**Study Type**

**RAPAMUNE**

**Formulation**

****

** ****1 year**

**310**

**Pivotal**

**Tablet**

**212**

**Supportive**

**Solution**

**207, 210**

**Early Studies**

**(RAPA **

**vs CsA)**

**Solution**

## Sirolimus Target Concentration Ranges after Cyclosporine Withdrawal in Studies 212 and 310

**Set prospectively based on results from Phase II Studies 207 and 210**
**For sample analysis by Immunoassay, the ranges were**
**10 - 20 ng/mL (Study 212) **
**20 - 30 ng/mL (Study 310)**
**The adequacy of the prospective target ranges were supported by**
**Efficacy results **
**Mean sirolimus trough levels (18 vs 23 ng/mL)**

## Outcomes of Sirolimus Concentration Control Among Studies (RAPA Group)

## Sirolimus and Cyclosporine Trough Levels for Study 310 (RAPA Group)

**Sirolimus and Cyclosporine Trough Levels for Study 310 (RAPA Group)**

## Overall, the investigators were successful in this first RAPAMUNE trial that required the simultaneous adjustment of 2 drugs
Cyclosporine was eliminated in 50% of patients by Week 6 after randomization
The ability to achieve the sirolimus target range will improve as physicians gain more experience with cyclosporine withdrawal

**Cyclosporine was eliminated in 50% of patients by Week 6 after randomization**
**The ability to achieve the sirolimus target range will improve as physicians gain more experience with cyclosporine withdrawal**

**Comments Regarding the Rate of Cyclosporine Withdrawal in Study 310**

## A Mean RAPAMUNE Dose of 8 mg/day Maintained Sirolimus in the Target Range for Study 310 

**A Mean RAPAMUNE Dose of 8 mg/day Maintained Sirolimus in the Target Range for Study 310 **

**8.4**

**23.3**

## Implementation of Sirolimus TDM

**Frequency of blood sampling for sirolimus assays after randomization in Study 310**
**Number of days required to reach the target range in Study 310**
**Number of dose changes required to reach the target range in Study 310**
**Sirolimus TDM range**
**Availability of sirolimus assays**

## Frequency of Blood Sampling For SirolimusAssays After the Start of Cyclosporine Withdrawal(Study 310)

## Number of Days and Dose Changes Required to Achieve the Target Range in Study 310

## Sirolimus TDM Range

**The sirolimus TDM range was determined****based on**
**Distribution analyses of sirolimus trough levels among non-rejectors and rejectors**
**Clinical outcomes for Studies 212 and 310**

## Distributions of Average Sirolimus Trough Levels Among Non-Rejectors in Studies 310 and 212 (RAPAMUNE Groups)

## Distributions of Sirolimus Trough Levels Among Rejectors in Studies 310 and 212(RAPAMUNE Groups)

## Sirolimus TDM Considerably ReducedIntersubject Variability in Study 310 Compared to a Predicted 8-mg Fixed-dose Regimen

**Sirolimus TDM Considerably Reduced****Intersubject Variability in Study 310 Compared to a Predicted 8-mg Fixed-dose Regimen**

## RecommendedSirolimus TDM Range

**A sirolimus TDM range of 15 to 25 ng/mL (Immunoassay) is recommended based on**
**The distributions of sirolimus trough levels among non-rejectors and rejectors in Studies 310 and 212**
**The very similar clinical outcomes in Studies  310 and 212 with respect to graft survival, patient survival, and improved renal function within the RAPAMUNE treatment groups**

## 23 Bioanalytical Laboratories Measure  Sirolimus Concentrations

## Guidance In Using Sirolimus TDM

**Guidance will be provided to physicians with respect to **
**Algorithms for estimating both a new maintenance dose and a new loading dose **
**Maximum recommended dose per day**
**Timing of blood draws for dose adjustments**
**Action guidelines based on assay results**
**Limitations of TDM**

## Conclusions (I)

**Experience with sirolimus TDM (without concurrent cyclosporine administration) has been obtained in 4 clinical trials during 1 year post-transplant among 347 patients**
**Efficacy outcomes in the TDM groups were equivalent to their respective fixed dose groups**
**Pharmacokinetic data **_**and**_** clinical outcomes for Studies 310 and 212 defined the range of sirolimus trough concentrations for TDM**
**The results show that TDM can guide the safe and effective use of sirolimus **

## Conclusions (II)

**TDM **_**without**_** cyclosporine co-administration (proposed indication)**
**Recommended sirolimus TDM range**
**Immunoassay: 15 to 25 ng/mL**
**Chromatographic assay: 12 to 20 ng/mL**