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
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
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
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 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
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
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
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)– 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)