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Review
. 2016 Feb;9(1):9-22.
doi: 10.1111/cts.12386. Epub 2016 Feb 5.

Toward Optimum Benefit-Risk and Reduced Access Lag For Cancer Drugs in Asia: A Global Development Framework Guided by Clinical Pharmacology Principles

K Venkatakrishnan  1 , C Burgess  1 , N Gupta  1 , A Suri  1 , T Takubo  2 , X Zhou  1 , D DeMuria  1 , M Lehnert  1 , K Takeyama  2 , S Singhvi  1 , A Milton  1
Affiliations
Review

Toward Optimum Benefit-Risk and Reduced Access Lag For Cancer Drugs in Asia: A Global Development Framework Guided by Clinical Pharmacology Principles

K Venkatakrishnan et al. Clin Transl Sci. 2016 Feb.
No abstract available

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Figures

Figure 1
Figure 1
Bridging study approach to oncology drug development and registration in Asia. Ph 1, phase I; Ph 2, phase II; Ph 3, phase III; PD, pharmacodynamic; PK, pharmacokinetic; RP2D, recommended phase II dose range; RP3D, recommended phase III dose range.
Figure 2
Figure 2
Application of a population pharmacokinetic (PK) model‐based framework to interpret emerging PK data from an ongoing, phase I, dose‐escalation study in Asia. The thick black vertical lines mark the percentiles of the Western dose‐normalized exposure distribution and dose‐normalized exposures in individual patients in the Asia phase I study are shown as the shorter colored vertical lines. In Scenario A, the data indicate a higher dose‐normalized exposure in Asian patients whereas in Scenario B, there are no readily apparent differences between Asian and Western patients, suggesting a low risk for exposure‐related differences in dose between Asia and the West. AUC(0–tau),ss, area under the plasma concentration‐time curve from time zero to time tau at steady state.
Figure 3
Figure 3
Application of exposure‐safety analysis in interpreting clinical relevance of exposure differences between Asian and Western patient populations to guide determination of dose for Asia. (a) and (b) depict two representative scenarios illustrating the value of quantitatively understanding exposure‐toxicity relationships in interpreting the clinical relevance of pharmacokinetic (PK) differences between Asian and Western populations and guiding determination of the dose for Asia. In both panels, systemic exposures on the x‐axis are plotted as a percentage of the mean exposure at the Western clinical dose in Western patients. The solid lines are the estimated exposure‐toxicity relationships based on logistic regression analyses of Western clinical data, with the dashed lines representing the associated 95% confidence intervals. The solid and open circle symbols are positioned on the exposure‐safety relationship at the mean Western and Asian population exposures, respectively. AE, adverse event; DLT, dose‐limiting toxicities.
Figure 4
Figure 4
Rationale for lower Asian recommended dose of the investigational anticancer agent alisertib relative to the Western patient population. (a) Shows the steady‐state, dose‐normalized plasma concentration‐time profiles (mean + SD) in patients with advanced cancers in Asia (n = 34; red symbols and lines)54 in comparison to corresponding data in Western patients (n = 23; green symbols and lines).51 (b) Shows the estimated relationship between steady‐state area under the concentration‐time curve (AUC) and probability of dose‐limiting toxicity (DLT) for alisertib (with 95% confidence intervals) in Western patients.53 Overlaid are the AUC distributions at the Western recommended phase II dose (RP2D; 50 mg b.i.d.; green box plot, with green star at the geometric mean) and the projected distribution at this dose if administered to patients in Asia (red box plot, with red star at the projected geometric mean).
Figure 5
Figure 5
Exposure‐matched global clinical trial strategy to support drug development and registration in Asia in the setting of pharmacokinetic (PK)‐related dose differences. The scenario as illustrated here is for a global phase III trial with exposure‐matched regional dosing of patients enrolled in Asia. Not shown here but also equally applicable is an alternate scenario of exposure‐matched regional dosing in an Asia‐inclusive phase II study supported by earlier conduct and availability of the Asia phase I data. Ph 1, phase I; Ph 3, phase III; PD, pharmacodynamic; RP2D, recommended phase II dose range; RP3D, recommended phase III dose range.
Figure 6
Figure 6
Roadmap for prospective integration of pharmacokinetic (PK)/pharmacodynamic (PD) considerations and dose decisions in globalization of oncology drug development inclusive of Asia. DoseAsia, Dose for Asia; DoseWest, dose for West.
Figure 7
Figure 7
Cross‐functional considerations across the pharmaceutical research and development continuum for efficient global oncology drug development to enable timely delivery of anticancer therapies with optimized benefit:risk worldwide inclusive of Asia. ADME, absorption, distribution, metabolism, and excretion; PB‐PK, physiologically based pharmacokinetics; PD, pharmacodynamics; PK, pharmacokinetics.
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References

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