RT Journal Article
SR Electronic
T1 Systems pharmacological analysis of paclitaxel-mediated tumor priming that enhances nano-carrier deposition and efficacy
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.112.199109
DO 10.1124/jpet.112.199109
A1 Sihem Ait-Oudhia
A1 Robert M. Straubinger
A1 Donald E. Mager
YR 2012
UL http://jpet.aspetjournals.org/content/early/2012/10/31/jpet.112.199109.abstract
AB Paclitaxel (PAC)-mediated apoptosis decompresses and primes tumors for enhanced deposition of nanoparticulate agents such as pegylated liposomal doxorubicin (SSL-DXR). A quantitative pharmacokinetic/pharmacodynamic (PK/PD) approach was developed to analyze efficacy and identify optima for PAC combined with SSL-DXR. Using data extracted from diverse literature sources, Taxol® (Cre-pac) PK was described by a carrier-mediated dispositional model and SSLDXR PK was described by a two-compartment model with first-order drug release. A hybridphysiological, well-stirred model with partition-coefficients (Kp) captured intratumor concentrations. Apoptotic responses driving tumor priming were modeled using nonlinear, timedependent transduction functions. The tumor growth model employed net first-order growth- and death rate constants, two transit compartments that captured the temporal displacement of tumor exposure vs. effect, and apoptotic signals from each agent were used to drive cytotoxic effects of the combination. The final model captured plasma and intratumor PK data, apoptosis induction profiles, and tumor growth for all treatments/sequences. A feedback loop representing PACinduced apoptosis effects on Kp_DXR enabled the model to capture tumor-priming effects. Simulations to explore time- and sequence-dependent effects of priming indicated that PAC priming increased Kp_DXR 3-fold. The intratumor concentrations producing maximal- (Emax) and half-maximal effects were 18 and 7.2 μg/mL for PAC, and 17.6 and 14.3 μg/mL for SSL-DXR. The duration of drug-induced apoptosis was 27.4h for PAC and 15.8h for SSL-DXR. Simulations suggested that PAC administered 24h prior to peak priming could increase efficacy 2.5-fold over experimentally-reported results. The quantitative approach developed here is applicable for evaluating tumor-priming strategies employing diverse agents.