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1222

Poster presented at the 2014 Annual Meeting of the American Association of Pharmaceutical Scientists, November 2–6, 2014, San Diego, CA, USA

Evaluation of a Truncated Pharmacokinetic (PK) Sampling Approach to Estimate Steady State Exposures for the Gamma Secretase Inhibitor PF-03084014 Joseph Chen, BS1, M. Naveed Shaik, PhD2, Rossano Cesari, PhD3, Kenneth A. Kern, MD, MPH2

1University of California, San Diego, CA, USA; 2Pfizer Oncology, La Jolla, CA, USA; 3Pfizer Oncology, Milan, Italy

BACKGROUND⦁⦁ An increasing number of procedures is a growing problem in clinical trials.

From 1999 to 2005, study-related procedures rose substantially; unique study procedures increased by 6.5% and procedural frequency by 8.7% annually. 1

⦁– In an analysis of 49 phase I trials, there was a mean of 105 events (eg, blood draws, urine samples, electrocardiograms) per patient over the first 4 weeks of study.2

⦁– With the high number of samples required, compounded by the numerous visits, patient adherence has greatly suffered. Lack of patient adherence can negatively impact trial outcomes.

⦁⦁ Clinical trial–related testing burden for patients and study sites can be alleviated by reduced pharmacokinetic (PK) collections.

⦁– In oncology trials, the need for adequate sampling to characterize drug PK must be balanced with feasibility, such as patient- and site-related considerations.

⦁– If less burdensome collections can be shown to accurately predict exposure of the drug, it will likely improve adherence.

⦁⦁ Two alternative approaches to collecting intensive serial PK samples that can potentially be used to estimate drug exposure are trough concentration (Ctrough) and truncated time-point–based area under the concentration–time curve (AUC) from time zero to tau (AUCtau).

⦁⦁ Although population-based approaches are generally applied in larger phase II/III trials, the use of Ctrough as a direct measure of AUCtau was evaluated in the current analysis.

⦁⦁ Additionally, the impact of fewer PK collections to characterize the AUCtau was also assessed.

⦁– Within the linear terminal elimination phase, there is a possibility of omitting select collection times, while still retaining the ability to reliably estimate steady-state AUCtau.

⦁⦁ PF-03084014, a small molecule gamma-secretase inhibitor currently in clinical development, dosed twice a day (BID), has a median time to first occurrence of maximum serum concentration of ~1 h and exhibits first-order kinetics.2

⦁– In the first-in-patient phase I study in patients with advanced solid tumors, serial PK profiles and Ctrough samples were collected at steady-state.

⦁⦁ In this analysis, Ctrough was compared with AUCtau to determine correlation.

⦁⦁ For evaluation of truncated time-point AUCtau, 3 different truncations were compared with full AUCtau, estimated using all time points:

⦁– 12-h concentration replaced with predose concentration.

⦁– 12-h concentration replaced with predose minus the 10-h concentration.

⦁– 12-h concentration replaced with predose minus the 8- and 10-h concentrations.

⦁– The replacement of the 12-h concentration with the predose concentrations was based on the assumption that these would be similar at steady-state and there are no chronological differences in PK profiles following AM and PM dosing of PF-03084014.

⦁⦁ The truncated AUCs were then assessed for statistical difference.

OBJECTIVES⦁⦁ Evaluate if Ctrough is an adequate alternative measure to AUCtau.

⦁⦁ Evaluate if AUCtau using truncated time points is an adequate alternative measure to estimate steady-state AUCtau based on a full PK profile.

METHODS⦁⦁ Serial steady-state PK data collected on Cycle 1 Day 21 from 36 patients enrolled

in Study A8641014 were used in this analysis.

⦁⦁ The PF-03084014 dose range tested was 20–330 mg BID, with overall dose-proportional exposure observed.

⦁⦁ The relationship between Ctrough and AUCtau was evaluated.

⦁⦁ The impact of assigning the predose level as the 12-h postdose concentration and removing the 8- and 10-h PK time points on the AUCtau estimate was assessed.

⦁⦁ A mean change of <5% in truncated PK-based AUCtau estimate compared with AUCtau was chosen a priori as acceptable.

⦁⦁ Phoenix Build 6.3.0.395 (noncompartmental PK analysis; Pharsight Corporation, Mountain View, CA) and R Studio version 0.98.501 (statistical analysis; RStudio, Boston, MA) were used for the analysis.

RESULTS⦁⦁ Ctrough and AUCtau relationship was tested using Pearson’s product-moment

correlation coefficient and found to be well correlated (correlation coefficient 0.969, R2=0.939) (Figure 1).

Figure 1: Correlation of Ctrough and AUCtau Following Administration of PF-03084014

log Ctrough (ng/mL)

AUCtau vs Ctough with linear regression and 95% Cl (n=36)

y=3.8 + 0.87 · xR2=0.939

log

AU

C (n

g·h/

mL) 9

10

11

8

7

6

52 4 6 8

AUCtau=area under the concentration–time curve (AUC) from time zero to tau; CI=confidence interval; Ctrough=trough concentration.

⦁⦁ A one-way analysis of variance (ANOVA) showed no significant difference among the 4 groups (Table 1), F (3, 140)=0.006, P=0.999 (Figure 2).

Table 1: Comparison of Truncated Time-Point–Based PF-03084014 AUCtau

Truncated Time-Point–Based AUCtau

Dose-Normalized AUCtau (ng·h/mL/mg),

Mean (%CV)% Change in AUCtau

vs Reference

AUCtau from full PK profile (all time points)

52.3 (74.9) Reference

AUCtau replacing 12 h with 0 h 52.3 (75.0) –0.01

AUCtau replacing 12 h and excluding 10 h

52.8 (74.7) 1.16

AUCtau replacing 12 h and excluding 8 and 10 h

53.4 (73.5) 3.30

% Change in AUCtau = (Reference AUCtau – AUCtau) / Reference AUCtau x 100% AUCtau=area under the concentration–time curve over the dosing interval; CV=coefficient of variation

Figure 2: Comparison of Truncated Time-Point–Based AUCtau. Percent Over or Under Predicted Compared With AUCtau, Based on Full PK Profile

Perc

enta

ge o

ver o

r und

er

10

20

30

0

Replacing 12 hwith predose

–0.01%

Replacing 12 hminus 10 h

1.16%

Replacing 12 hminus 8 & 10 h

3.3%

AUCtau=area under the concentration–time curve from time zero to tau (over the dosing interval); PK=pharmacokinetics

⦁⦁ The R2 value for the AUCtau replacing the 12-h concentration with predose concentration was 0.999, the AUCtau replacing the 12-h minus 10-h concentration was 0.996, and the AUCtau replacing the 12-h minus 8- and 10-h concentration was 0.995 (Figure 3).

⦁⦁ Although the R2 value decreased slightly as more time points were removed, all truncated time-point AUCtau appeared to be good predictors of AUCtau using all serial sampling points.

Figure 3: Dose-Normalized Truncated Time-Point AUCtau vs Dose-Normalized AUCtau, Based on Full PK Profile

Replacing 12 hwith predose

Replacing 12 hminus 10 h

Replacing 12 hminus 8 & 10 h

Dos

e-no

rmal

ized

AU

C al

l (ng

·h/m

L/m

g)

150

100

50

200

50 100 150 50 100 150 50 100 150Dose-normalized AUC (ng·h/mL/mg)

R2=0.999 R2=0.996 R2=0.995

AUCtau=area under the concentration–time curve (AUC) from time zero to tau (over the dosing interval); PK=pharmacokinetics

REFERENCES1. Kurzrock R, Stewart DJ. Compliance in early-phase cancer clinical trials research. The Oncologist 2013;18:308-13. 2. Messersmith WA, Shapiro GI, Cleary JM, et al. A phase I, dose-finding study in patients with advanced solid malignancies

of the oral gamma-secretase inhibitor PF-03084014. Clin Cancer Res 2014;21(2);1-9.

DISCLOSURES This study was sponsored by Pfizer Inc. M.N. Shaik, R. Cesari, and K.A. Kern were full-time employees of Pfizer Inc and J. Chen was a contractor of Pfizer Inc during the conduct of this study. Editorial support was provided by S. Mariani, MD, PhD, of Engage Scientific Solutions, and was funded by Pfizer Inc.Copyright © 2014.

ABSTRACTPurpose: In oncology trials, the need for adequate sampling to characterize drug pharmacokinetics must be balanced with feasibility, such as patient and site convenience. While population-based approaches are generally applied in larger trials, the use of trough concentration (Ctrough) as a direct measure of area under the concentration–time curve (AUC) from zero to tau (AUCtau) was evaluated. The impact of fewer pharmacokinetic (PK) collections was also assessed. Within the linear terminal elimination phase, select times can be omitted while still retaining the ability to estimate steady-state AUCtau.

PF-03084014, a small molecule gamma-secretase inhibitor in clinical development, dosed twice daily, has a median time to reach maximum concentration (Tmax) of 1 h and exhibits first-order kinetics. In the first-in-patient study, serial PK profiles and Ctrough samples were collected at steady-state.

Methods: Serial steady-state PK data from 36 patients on Cycle 1 Day 21 was used. The relationship between Ctrough and AUCtau was evaluated. Furthermore, the impact of assigning the predose level as the 12-h postdose concentration and removing the 8 and 10 h PK time points on the AUCtau estimate were assessed. A mean change of <5% in estimated AUCtau was considered acceptable. Phoenix Build 6.3.0.395 (PK analysis) and R Studio version 0.98.501 (statistical analysis) were used.

Results: Ctrough and AUCtau were highly correlated (correlation coefficient 0.969) and regression indicated that Ctrough was a valid surrogate for AUCtau. A one-way ANOVA showed no significant difference among the 4 groups (Table 1), F (3, 140) = 0.006, P=0.999.

Differing by a small percentage, these truncated time-point AUCs serve as a reasonable surrogate measure for actual AUCtau.

Conclusion: For PF-03084014, Ctrough is a reasonable surrogate for AUCtau. AUCtau can be estimated with truncated PK sampling. Using a limited PK collection approach for oncology patients, ie, 4-h sampling instead of 12-h for PF-03084014, will allow for better patient compliance, fewer samples collected (and associated collection errors), and sites being more receptive to PK sampling. Overall, a marginal (<4%) reduction in accuracy in estimating AUCtau is outweighed by the benefits of using this approach for drugs with longer plasma half-lives.

CONCLUSIONS⦁⦁ For PF-03084014, Ctrough is a reasonable surrogate for AUCtau. AUCtau can be

well estimated with truncated PK sampling.

⦁⦁ Using a limited PK collection approach for oncology patients, ie, 4-h sampling instead of 12-h sampling for PF-03084014, will allow for substantially better patient compliance, fewer samples collected (and associated collection errors), patients will only be needed at the clinical site for a third of the time currently required, and study sites more receptive to PK sampling.

⦁⦁ Overall, a marginal (<4%) reduction in accuracy in estimating AUCtau is outweighed by the benefits of using this approach for drugs with longer half-lives.