Challenges of Pharmacokinetic/Pharmacodynamic Assessments in Pediatric Oncology

1
Challenges of Pharmacokinetic/Pharmacodynamic
Assessments in Pediatric Oncology
Clinton F. Stewart, Pharm.D. St. Jude Childrens
Research Hospital Memphis, TN
2
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

3
Pharmacology Studies EnhanceDevelopment of
Anticancer Drugs

• Additional PK/PD (efficacy) studies
• Evaluate different schedules

Phase IV Clinical Trials
Phase II Clinical Trials
Phase III Clinical Trials
MARKET

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

• Comparative studiesof efficacy

4
Two Commercially Available Topoisomerase I
Inhibitors For Use In Pediatric
OncologyTopotecan and Irinotecan
5
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

6
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

7
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 variabilityin clearance with
  small (20) dosage increments, overlap in
  topotecan exposure across dose levels

8
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

9
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)

10
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

11
Application of Nonclinical PK/PD StudiesEnhance
Anticancer Drug Development

• Additional PK/PD (efficacy) studies
• Evaluate different schedules

Phase II Clinical Trials

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

12
Role of Pharmacokinetics in Xenograft Model
Topoisomerase I Inhibitors
13
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

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

• Clinical dosing schedule low-dose, protracted
  (dx5x2)

14
Use of the Nonhuman Primate Model
Topotecan in CNS Malignancies

• 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

15
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

16
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
17
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

18
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.,
  gt 24 hr CI, gt 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

19
Application of Pharmacokinetic Studies to
Optimize Topotecan Therapy Design Considerations

• Selection of initial systemic exposure and dose

• Pharmacokinetic metric to express drug exposure

20
Topotecan Dosage Adjustment Schema TOPO5x2
PK Studies
Adjust Dose

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

21
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

22
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 (gt 50 PR)
• Achieve target exposure (gt90) ? interpt var.
  TPT AUC
• Studied 10 infants (lt 2 yr), noted TPT lactone
  systemic clearance significantly lt 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
  plasmatarget CSF)
• Manageable toxicities
• Drug-drug interactions
• Enzyme-inducing anticonvulsants (DPH) increase
  TPT clr
• Dexamethasone increases TPT clr

23
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

24
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)
• IC50 vs AUC vs some other measure of drug
  exposure
• Important to consider that pediatric tumors
  likely have different biological pathways and
  therefore targets

25
Challenges in Pharmacokinetic/Pharmacodynamic
Assessments in Pediatric Oncology

• Havent 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
  weve 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)