# Presentation: 546918

## Challenges of Pharmacokinetic/Pharmacodynamic Assessments in Pediatric Oncology

**Clinton F. Stewart, Pharm.D.**
**St. Jude Children’s Research Hospital**
**Memphis, TN**

## Outline

**Summary of results of early clinical pharmacokinetic studies with topoisomerase I inhibitors **
**Application of results from nonclinical studies of topoisomerase I inhibitors to design of clinical trials (Phase Ib/IIa)**
**Summary results of later clinical drug development with topoisomerase I inhibitors (Phase Ib/Phase IIa)**
**Thoughts regarding design of clinical pharmacokinetic studies of “targeted” drug therapy**

## Pharmacology Studies EnhanceDevelopment of Anticancer Drugs

**Phase IV**
**Clinical **
**Trials**

**Phase II**
**Clinical **
**Trials**

**Phase III**
**Clinical **
**Trials**

**MARKET**

-  **Additional PK/PD (efficacy) studies**
** ****Evaluate different schedules**

** ****Evaluate clinical safety of ****new schedules, dosage, ****or combinations**

** ****Comparative studies****of efficacy**

## Two Commercially Available Topoisomerase I Inhibitors For Use In Pediatric Oncology:Topotecan and Irinotecan

## Initial Clinical Trials with Topoisomerase I Inhibitors in Children with Cancer

**Topotecan 72-hour CI in children with recurrent solid tumors (Pratt, *****JCO*****, 1994)**
**Antitumor activity***
**DLT myelosuppression**
**Preliminary data for **_***LSM***_

**Topotecan 120-hour CI in children with recurrent leukemia (**_***MTSE***_**) (Furman, *****JCO*****, 1996)**
**Antileukemic effect***
**DLT mucositis**
**PK/PD observations**

## Initial Clinical Trials with Topoisomerase I Inhibitors in Children with Cancer

**Oral topotecan (15 or 21-days) in children with refractory solid tumors (Zamboni, *****CCP*****, 1999)**
**Well absorbed**
**Wide interpatient variability but less than intrapatient**

**Topotecan CSF penetration studied in children with primary brain tumors (Baker, *****CCP*****, 1996)**
**Extensive penetration, wide interpatient variability, no difference among infusion rates**

## Initial Clinical Trials with Topoisomerase I Inhibitors in Children with Cancer

**Topotecan 30-min infusion (dx5) in children with recurrent solid tumors (POG-9275; Tubergen, Stewart *****JPHO*****, 1996)**
**Antitumor activity**
**DLT myelosuppression**
**Validation of LSM**
**Wide interpatient variability****in clearance with small (~20%) dosage increments, overlap in topotecan exposure across dose levels**

## Initial Clinical Trials with Topoisomerase I Inhibitors in Children with Cancer

**Irinotecan 60-min infusion (dx5x2) in children with recurrent solid tumors (Furman, *****JCO*****, 1999)**
**Antitumor activity**
**DLT diarrhea**
**Pharmacokinetics complex with metabolism to active (SN-38) and inactive metabolites**
**SN-38 highly protein bound**
**Role for pharmacogenetics**

## Comparison of Results from Adult and Pediatric Phase I Studies for the Topoisomerase I Inhibitors

**Pharmacokinetics**
**Topotecan lactone systemic clearance similar between adults and children, in early studies***
**Limited pediatric population (ages, drug-drug intxn)**
**Pharmacodynamics**
**Relation between TPT lactone systemic exposure and %decrease ANC similar between two groups**
**MTD**
**Pediatric MTD higher for comparable schedules; problematic comparison (dx5x2)**
**DLT (no difference)**

## Outline

**Summary of results of early clinical pharmacokinetic studies with topoisomerase I inhibitors**** **
**Application of results from nonclinical studies of topoisomerase I inhibitors to design of clinical trials (Phase Ib/Iia)**
**Summary results of later clinical drug development with topoisomerase I inhibitors (Phase Ib/Phase Iia)**
**Thoughts regarding design of clinical pharmacokinetic studies of “targeted” drug therapy**

## Application of Nonclinical PK/PD StudiesEnhance Anticancer Drug Development

**Phase II**
**Clinical **
**Trials**

-  **Additional PK/PD (efficacy) studies**
** ****Evaluate different schedules**

** ****Evaluate clinical safety of ****new schedules, dosage, ****or combinations**

## Role of Pharmacokinetics in Xenograft Model

**Role of Pharmacokinetics in Xenograft Model**

***Topoisomerase I Inhibitors***

## Summary of Topoisomerase I Antitumor Efficacy Studies Conducted in the Xenograft Model 

** **_**Schedule-dependent**_
**Duration of therapy critical**
**Administration interval important **
***Protracted dosing schedule***** associated with antitumor activity**

_**Clinical dosing schedule**_**: low-dose, protracted (*****dx5x2*****)**

** **_**Dose-dependent**_
**Self-limiting antitumor activity at high doses**
***Critical threshold drug exposure***** for antitumor activity**

## Use of the  Nonhuman Primate Model

**To evaluate effect of TPT infusion rate on TPT CSF concentration throughout the neuraxis (ventricular & **_***lumbar***_**)**

**To generate a PK model to describe plasma and CSF TPT disposition, which could be used to design clinical trials of TPT to treat CNS tumors**

_***Topotecan in CNS Malignancies***_

## Outline

**Summary of results of early clinical pharmacokinetic studies with topoisomerase I inhibitors**** **
**Application of results from nonclinical studies of topoisomerase I inhibitors to design of clinical trials (Phase Ib/Iia)**
**Summary results of later clinical drug development with topoisomerase I inhibitors (Phase Ib/Phase Iia)**
**Thoughts regarding design of clinical pharmacokinetic studies of “targeted” drug therapy**

## Rationale for Pharmacokinetically Guided Dosing of Anticancer Drugs

**Considerations for this relationship**
**Preclinical models**
**Clinical studies**
**Drug sensitive tumor**
**Systemic-intensity not same as dose intensity**
**Medication errors**
**Patient tolerance**
**Patient compliance**

***Dose intensity***

***Clinical Response***

***Systemic Exposure***

## Rationale for Pharmacokinetically Guided Dosing in Children with Cancer

**Pharmacokinetic variability**
**Drug absorption, distribution, metabolism, & elimination**
**Inter-patient variability greater than intrapatient**

**Other sources of variability**
**Maturational changes**
**Renal & hepatic impairment**
**Inherited difference in drug metabolism & disposition**
**Drug-drug intxns**

## Selected Criteria for Pharmacokinetically Guided Dosing

**General considerations**
**Narrow therapeutic index**
**Drug effect delayed **
**Relation between drug effect & drug exposure**
**Logistical considerations**
**Drug regimen amenable to dosage adjustment (e.g., > 24 hr CI, > 1 d regimen [dx5x2], etc.)**
**Assay method available**
**Pharmacokinetic considerations**
**Well-characterized pharmacokinetics (PK model)**
**Population priors for available for Bayesian analysis**
**Limited sampling model**

## Application of Pharmacokinetic Studies to Optimize Topotecan Therapy: Design Considerations

**Selection of initial systemic exposure and dose**

**Pharmacokinetic metric to express drug exposure**

## Topotecan Dosage Adjustment Schema

**TOPO5x2**

** ****Topotecan i.v. over 30 minutes daily x 5 for two consecutive weeks**
** ****Target topotecan systemic exposure 100 ± 20 ng/ml-hr**

**PK **
**Studies**

**Adjust**
**Dose**

## Lessons Learned from Pharmacokinetically Guided Topotecan Clinical Trials

**Phase I Feasibility Study (TOPO5x2)**
**Antitumor activity noted**
**Achieve target systemic exposure and reduce interpatient variability in topotecan exposure**
**Pharmacokinetically guided TPT in combination with vincristine (*****Phase I*****)**
**Some antitumor responses**
**However, significant myelosuppression (platelets)**
**Used lower topotecan target (80 ± 10 ng/mL)**
**Pharmacokinetically guided TPT in combination with CTX (*****Phase I*****)**
**Used as a conditioning regimen followed by AHSCT**
**Toxicities manageable**
**~90% patients were within “target”**

## Lessons Learned from Pharmacokinetically Guided Topotecan Clinical Trials

**PK guided TPT dosing: upfront window therapy (**_***Phase II***_**) in children with  high-risk neuroblastoma (SJNB97)**
**No progressive disease noted (> 50% PR)**
**Achieve target exposure (>90%) & ******** interpt var. TPT AUC**
**Studied 10 infants (< 2 yr), noted TPT lactone systemic clearance significantly < than in other pts (12 vs 21 L/hr)**
**PK guided TPT dosing: upfront window therapy (*****Phase II*****) in children with high-risk medulloblastoma (drug exposure in a “minor” exposure compartment, i.e., CSF)**
**Significant antitumor response (target plasma~target CSF)**
**Manageable toxicities**
**Drug-drug interactions**
**Enzyme-inducing anticonvulsants (DPH) increase TPT clr**
**Dexamethasone increases TPT clr**

## Outline

**Summary of results of early clinical pharmacokinetic studies with topoisomerase I inhibitors**** **
**Application of results from nonclinical studies of topoisomerase I inhibitors to design of clinical trials (Phase Ib/Iia)**
**Summary results of later clinical drug development with topoisomerase I inhibitors (Phase Ib/Phase Iia)**
**Thoughts regarding design of clinical pharmacokinetic studies of “targeted” drug therapy**

## Design Issues for Molecular Target-Based Anticancer Drugs in Children

**Definition of “target”**
**Expression of protein *****in vivo***
**Expression of protein and data from *****in vitro***** studies**
**Expression of protein, data from *****in vitro***** studies, and prognostic significance**
**Emphasizes the need for a “relevant” model in which to evaluate the “target”**
**In vitro, xenograft, transgenic**
**Requires a complete understanding of pathway(s)**
**Pharmacologic metric (as with PK guided dosing)**
**IC****50**** vs AUC vs some other measure of drug exposure**
**Important to consider that pediatric tumors likely have different biological pathways and therefore targets**

## Challenges in Pharmacokinetic/Pharmacodynamic Assessments in Pediatric Oncology 

**Haven’t really talked a lot about “challenges” per se because:**
**Resources and infrastructure of St. Jude have made these studies possible**
**Also, the infrastructure present in the DT Committee, COG**
**Challenge for the future to apply what we have learned to Phase IIb/III clinical trials of topotecan used in combination**
**COG study of topotecan in combination with CTX in NB**
**How to dose topotecan? **
**Topotecan population pharmacokinetic study, where we’ve found that covariates for TPT clearance included BSA, concomitant phenytoin therapy, serum creatinine, and age**
**PK studies provide insight into differences in drug disposition (phenotype) which can then be explained in many cases by genetic variations in drug metabolism or transport (genotype)**