challenges of pharmacokinetic/pharmacodynamic assessments in pediatric oncology clinton f. stewart,...

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 EnhanceDevelopment of Anticancer Drugs

Phase IVClinical

Trials

Phase IIClinical

Trials

Phase IIIClinical

Trials

NonclinicalPK/PD

Studies

Phase IClinical

Trials MA

RK

ET

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

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

• Comparative studiesof 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

0.0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4 5 6

TPT Lactone Plasma Systemic Exposure (Cpss)

Res

po

nse

(Pro

po

rtio

n o

f Co

urs

es)

Oncolytic Response

Mucositis

TOPO-L

Topotecan 120-hour CI in children with recurrent leukemia (MTSE) (Furman, JCO, 1996)

–Antileukemic effect*–DLT mucositis–PK/PD observations


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

less than intrapatient

0

0.2

0.4

0.6

0.8

1

To

po

tec

an

CS

F P

en

etr

ati

on

0.5-hr 24-hr 72-hr

Topotecan CSF penetration studied in children with primary brain tumors (Baker, CCP, 1996)–Extensive penetration, wide

interpatient variability, no difference among infusion rates


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


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


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)


Application of Nonclinical PK/PD StudiesEnhance Anticancer Drug Development

Phase IIClinical

Trials

NonclinicalPK/PD

Studies

Phase IClinical

Trials

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

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

Phase IVClinical

Trials

Phase IIIClinical

Trials MA

RK

ET

• Comparative studiesof efficacy

Xenograft models in Preclinical Testing

[(d x 5)2]3 1 mg/kg

Schedules Doses

time

SystemicExposure

time

time

Role of Pharmacokinetics in Xenograft ModelTopoisomerase 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

Objectives

LateralVentricle

4thVentricle

Medulla Cerebellum

CSF

Lateral VentricularCatheter

4thVentricleCatheter

ChoroidPlexus

Topotecan in CNS Malignancies

Outline





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

Dose intensity Clinical ResponseSystemic Exposure

Rationale for Pharmacokinetically Guided Dosing in Children with Cancer

Pharmacokinetic variability–Drug absorption, distribution,

metabolism, & elimination–Inter-patient variability

greater than intrapatient

10 20 30 40 50 60 70

Topotecan Systemic Clr (L/hr/m2)

# C

ou

rses

of

Th

erap

y

7-Fold Range In TPT Clearance

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

0.1

1

10

100

1000

0 1 2 3 4 5 6

Time (hr)

TPT L

acto

ne C

onc (

ng/m

L)Time Above Threshold Exposure in CSF

Area under the concentration-time curve (AUC) in plasma

Pharmacokinetic metric to express drug exposure

Topotecan Dosage Adjustment SchemaTOPO5x2

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

PK Studies

AdjustDose

X XDose

Day 1 2 3 4 5 6 7 8 9 10 11 12

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





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

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)

challenges of pharmacokinetic/pharmacodynamic assessments in pediatric oncology clinton f. stewart,...

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