Slides faod - the other mitochondrial energy diseases - vockley
ABirg- PK of Oral Topo (1)
1. Pharmacokinetics of Oral Topotecan in
Infants and Young Children with Brain
Tumors
Anna Birg
Pharmaceutical Sciences Department
Dr. Stewart Lab
2. Treatment of Primary CNS Tumors
in Infants and Children
• Surgery
– Limited by tumor location
• Radiation
– Neurocognitive and endocrine problems
• Chemotherapy
– Some active cytotoxic agents
– Need for optimization of therapy
6. Topotecan Pharmacokinetics
• Absorption: 30-40% oral bioavailability
– 27% oral bioavailability
• Distribution (oral): V1/F 40.6 L
– V1/F 33.8 L/m2 Vd
• Metabolism: <10% hepatic to metabolism
to N-desmethyl topotecan
• Elimination: 20% oral and 49% IV urinary
excretion
– 67.5% ± 25.2% IV urinary excretion
Leger, British J of Cancer, 2004 Herben, cancer chemother pharmacol
Daw, J of Clinical Oncology, 2004 Stewart, J Clin Oncology, 1994
Bai, J Chromat, 2003
7. Topotecan in Pediatrics
• High interpatient variability
– Ka (53%)
• BSA is a significant covariate on Cl and Vd
– IV topotecan
• Some evidence suggests that topotecan
Cl may be lower in infants
Daw, J of Clinical Oncology, 2004
Schaiquevich, Clin Cancer Res, 2007
9. Oral Topotecan in SJYC07
• 0.8 mg/m2
• Mixed with a liquid or flavored syrup
(cherry, chocolate, etc.)
10. Sample Collection and Analysis
• Collected on day 1 of first course
• Bedside processing
• HPLC with fluorescence detection
– Topotecan lactone
– 1 ng/mL LLOQ
11. Demographics
Patient
Characteristic n Mean Median Range
Age (years) 69 2.36 2.37 0.48 - 4.59
Weight (kg) 69 12.60 12.40 5.20 - 17.50
Height (cm) 69 87.19 89.10 59.5 - 102
BSA (m2) 69 0.57 0.57 0.31 - 0.72
eGFR
(mL/min/1.73
m2) 50 150.32 140.50 99.12 - 202.58
Sex 69
Male 42
Female 27
12. Pharmacokinetic Analysis
• Nonlinear mixed-effects modeling in
Monolix 4.3.2
– Stochastic approximation expectation
maximization algorithm (SAEM) + Markov
Chain Monte Carlo (MCMC)
• BLQ data was treated as quantified data
13. Population Modeling
• One and two compartment models evaluated
• Constant, proportional, combined, exponential residual
error models
• Covariate analysis via forward addition and backward
elimination
– Sex
– Age
– BSA
– Weight
– Height
– eGFR
• Ka, V/F, Cl/F
14. Final Model
𝐶𝑙/𝐹𝑖 = 𝐶𝑙/𝐹𝑝𝑜𝑝 ∗
𝐵𝑆𝐴𝑖
𝐵𝑆𝐴 𝑝𝑜𝑝
𝜃
Parameters
Mean Parameter
Estimate
Standard
Error
Residual Standard
Error (%)
ka (h-1) 0.395 0.029 7
V/F (L) 23.2 4.1 18
Cl/F (L/h) 41.6 2.8 7
θ 1.22 0.4 33
ω-BSV
ka 0.0775 0.26 335
V/F 0.983 0.12 12
Cl/F 0.463 0.058 13
σ-RUV 0.461 0.045 10
18. Discussion and Conclusions
• No significant effect of age on Ka
– One sample to characterize Ka
– BLQ data
• eGFR was not a significant covariate
– All patients had normal renal function
• BSA was significant on Cl/F
– Both height and weight were significant on
Cl/F
– Age on Cl/F
20. Thank you!
• Jessica Roberts
• Dr. Stewart
• University of Tennessee College of Pharmacy
Editor's Notes
-Medulloblastoma, supratentorial primitive neuroectodermal tumor (PNET), atypical teratoid/rhabdoid tumor (ATRT), high grade glioma, choroid plexus carcinoma (CPC), ependymoma
- CSI can lead to cognitive and endocrine problems
- Want to delay CSI in children less than 3 do chemotherapy and focal radiotherapy (focal RT)
Optional maintenance phase
Pts also getting oral cyclo along with oral topo
Maintenance cycle A, days 1-10 (cyclo is also given during this time on days 1-21) rest from days 22-28 next cycle (B) is erlotinib or etoposide (days 1-28)
Repeats 3 times (3 A cycles, 3 B cycles, each 28 days long)
Cyclophosphamide is also highly active against medulloblastoma and other embryonal tumors,14,93 and the combination of cyclophosphamide and topotecan has been effective in the treatment of metastatic Ewing’s sarcoma and other pediatric
solid tumors.94,95
Camtothe-SIN
extensive antitumor activity in preclinical studies, including xenograft models of pediatric CNS tumors such as medulloblastoma.87-89
Used for ovarian cancer and small cell lung cancer
Activity is dependent on proportion of cells actively dividing- S phase
Oral dosing mimics the protracted schedule that is optimal for cytotoxicity (should be prolonged and repeated and not a continuous infusion)
Vds- which compartment
Vd=0.58* body weight (kg)- Leger, British J of Cancer, 2004
Verify which adult studies were oral and if they need /m2
Main bullet= adult
Second bullet= pediatrics
Phase I and II study of topo (Najat C. Daw)
Effect of age on ka (younger children have less oral absorption)
Maturation: (infants have higher gastric pH), longer gastric emptying time, different drug metabolizing enzymes, changes in biliary function based on age
every effort should be made to obtain samples within 15 minutes before or after the schedule time point. The PK nurse administering the drug should estimate the proportion of the drug swallowed. If <75% of the dose was swallowed, PK testing should be rescheduled for another day during week 1 of cycle A1.
- Dose was given between 8 am-12:30 pm
2 mL of blood
69 patients total (1 data point was eliminated because PWRES > 6)
206 samples
Schwartz equation- why that one was chosen (used in the clinic; shown to be better for kidney dysfunction)
eGFR from SCr (Schwartz equation)
𝑒𝐺𝐹𝑅= 0.413 ∗ height (cm) SCr (mg/dl)
- Measuring totals were also BLQ
BSA on Cl was significant- equal significance as weight and height
Continuous covariates (BSA) was power model centered on population median
Categorical (sex) was exponential model
Inter-individual variability model- exponential
Residual undefined variability- proportional
CL/Fi : individual apparent clearance
CL/Fpop: estimated population apparent clearance
BSAi : individual body surface area
BSApop: median population body surface area
Θ: estimated exponent for the effect of body surface area on topotecan lactone clearance
Omega between subject variability
Sigma residual subject variability
One compartment model adequately characterizes oral topotecan disposition
Observed vs predicted
Observed topo lactone on y axis; population/individual predicted on x axis
Still some underprediction in model (population predicted)
Individual predicted- not as much of an underprediction
Red line: spline
Line of identity: ideal
Population weighted residual & individual weighted residual (y axes)
Time and predicted topotecan lactone (x axes)
Majority of data between +2 and -2 (within the acceptable predicted range)
Equal distribution both above and below the reference line
Time and predicted lactone concentrations are plotted- no bias (either in the time points or the concentrations)- no significant bias based over time or range of predicted lactone concentrations
Reference line
Residuals= how far away the point is from the line of ID (want it to be within 2 fold of a difference- negative means model is overpredicting, positive means model is underpredicting)
Normalized Prediction Distribution Errors
Simulations- 500
+2 and -2
Equal distribution
No bias
Mean=0; variance=1 (variance shouldn’t be lower than 0.8- model is underpredicting variance)
Ka: ideally, more samples after first dose, but this isn’t really practical in this population
BSA on Cl: since that’s what the dose is based off of, we used BSA
eGFR: all pts had normal renal function, not all pts had a SCr measurement
Average SCr was used to calculated GFR (for pts that didn’t have SCr measurements
Age on Cl: was significant initially during forward addition; potential maturation effect or size effect; but BSA on Cl ended up being most significant, so age is a surrogate for size
Bioavailability: pts that consented to maintenance PK studies- use their IV topo
Genetic
ABCB1= PGP- substrate for PGP (PGP inhibitors affect oral bioavailability)- no effect
ABCG2= BCRP- found a SNP that was correlated with increased ka increased Cmax
