ABOUT OUR COMPANY

Therapeutic Drug Monitoring (TDM) and Chemotherapies:

TDM is predicted to be most effective against drugs with highly variable PK- a characteristic of paclitaxel. Paclitaxel has more than 10X variability in patient exposure (1-3). Various patient-related factors can affect drug pharmacokinetics (PK), for example organ function, expression and activity of metabolizing enzymes, drug resistance, body size, gender, age, concomitant disease and co-administration of other drugs. These factors may be of clinical significance in chemotherapy dose determination. Paclitaxel is metabolized and excreted eliminated by the liver (4,5); therefore, hepatic impairment impacts on the clearance of drug from circulation and P-glycoprotein (Pgp) status, a transmembrane active efflux pump for a variety of drugs, impacts on the clearance of drug and its resorption in the gut. Hepatic clearance is further influenced by CYP family of enzymes that play a major role in drug metabolism (6). Additionally, there are other factors which are inherent to the use of body surface area (BSA) as dose normalizer (7). BSA itself is affected by weight; paclitaxel AUC increases proportionally with weight due to increase in total dose in heavier patients. As a consequence, Caucasians tends to have higher AUCs than Asians. The effect of age―as most patients are elderly―has not been adequately analyzed.

For paclitaxel, there exists a large inter-individual variation in pharmacokinetics, for AUCinf (area under the plasma concentration time curve from time zero extrapolated to the infinite time), the average coefficient of variation (CV) is in the range of 20-50% (4,8,10-12). The cause of this large variation is not completely understood and therefore cannot be controlled for. Hepatic impairment and obesity have been identified as contributing factors; however, other unknown factors remain to be defined. Looking at paclitaxel PK, it is apparent that patients dosed with the approved dose, have a high chance of being either underdosed or overdosed (9).

The highly variability of paclitaxel PK does have a significant impact on its therapeutic application. In two studies where paclitaxel dose of 100 mg/m2 was compared to paclitaxel dose of 125 mg/m2, the higher-dosed group did better than the lower-dosed group (13,14). Given the high variability of paclitaxel PK, it is highly probable that identification of patients who are under-dosed and moving them to a higher dose would result in more than a 25% increase in drug exposure. This is a strong argument for TDM as diagnostic biomarker for paclitaxel.

OnDose, manufactured by Saladax/Myriad, is an ELISA blood test that helps oncologists optimize infusional 5-FU therapy on an individual basis. Like paclitaxel, 5-FU is a chemotherapeutic agent with highly variable PK. OnDose provides the data for pharmacokinetically-guided dose adjustments of infusional 5-FU to help optimize dosing for patients with colorectal cancer. In a phase 3, multicenter, randomized study (N=208), optimized dosing demonstrated proven benefits for both efficacy and toxicity (15). Half of the patients were dosed with 5-FU based on BSA. The other half were initially dosed based on BSA, with subsequent cycle doses adjusted based on blood tests that measured the actual concentration of chemotherapy in the patients’ blood plasma. The primary and secondary endpoints were tumor response and treatment tolerance, respectively. The study concluded that: 1) Response rates were nearly doubled in the dose-adjusted group versus the BSA group (33.6 percent versus 18.3 percent) with statistical significance; 2) Overall survival at two years among patients with personalized 5-FU dose management improved by 48 percent with an improved median survival of 22 months versus 16 months in the BSA arm. The survival data was leaning towards significance; 3) Grade III/IV 5-FU related toxicities were found to be significantly lower in patients with personalized dose adjustment; 4) 58 percent of patients were found to be under-dosed (sub-therapeutic and less effective drug levels) and had their doses adjusted upward; and 5) 17 percent were found to be over-dosed (increasing the risk of severe side effects) and had their doses adjusted downward.

References:

• 1) Evans, W. E. &Relling, M. V. Clinical pharmacokinetics-pharmacodynamics of anticancer drugs. Clin. Pharmacokinet. 16, 327-336 (1989)
• 2) Freyer, G. et al. Pharmacokinetic studies in cancer chemotherapy: usefulness in clinical practice. Cancer Treat. Rev. 23, 153-169 (1997)
• 3) Masson, E. & Zamboni, W. C. Pharmacokinetic optimisation of cancer chemotherapy: effect on outcomes. Clin. Pharmacokinet. 32, 324-343 (1997)
• 4) Sparreboom A, Scripture CD, Trieu V, Williams PJ, De T, Yang A, Beals B, Figg WD, Hawkins M, Desai N. Comparative preclinical and clinical pharmacokinetics of a cremophor-free, nanoparticle albumin-bound paclitaxel (ABI-007) and paclitaxel formulated in Cremophor (Taxol). Clin Cancer Res. 11, 4136-43 (2005)
• 5) Sparreboom A, van Tellingen O, Nooijen WJ, Beijnen JH. Tissue distribution, metabolism and excretion of paclitaxel in mice. Anticancer Drugs. 7, 78-86 (1996)
• 6) Walle T. Assays of CYP2C8- and CYP3A4-mediated metabolism of taxol in vivo and in vitro. Methods Enzymol, 272, 145-51 (1996)
• 7) Baker, S. D. et al. Role of body surface area in dosing of investigational anticancer agents in adults, 1991-2001. J. Natl. Cancer Inst. 94, 1883-1888 (2002).
• 8) Nyman DW, Campbell KJ, Hersh E, Long K, Richardson K, Trieu V, Desai N, Hawkins MJ, Von Hoff DD. Phase I and pharmacokinetics trial of ABI-007, a novel nanoparticle formulation of paclitaxel in patients with advanced nonhematologic malignancies. J ClinOncol. 23, 7785-93 (2005)
• 9) Mielke S. Individualized pharmacotherapy with paclitaxel. CurrOpinOncol 19, 586-9 (2007)
• 10) Yamada K, Yamamoto N, Yamada Y, Mukohara T, Minami H, Tamura T. Phase I and pharmacokinetic study of ABI-007, albumin-bound paclitaxel, administered every 3 weeks in Japanese patients with solid tumors. Jpn J ClinOncol. 40:404-11 (2010).
• 11) Gardner ER, Dahut WL, Scripture CD, Jones J, Aragon-Ching JB, Desai N, Hawkins MJ, Sparreboom A, Figg WD. Randomized crossover pharmacokinetic study of solvent-based paclitaxel and nab-paclitaxel. Clin Cancer Res. 14: 4200-5 (2008).
• 12) Stinchcombe TE, Socinski MA, Walko CM, O'Neil BH, Collichio FA, Ivanova A, Mu H, Hawkins MJ, Goldberg RM, Lindley C, Claire Dees E. Phase I and pharmacokinetic trial of carboplatin and albumin-bound paclitaxel, ABI-007 (Abraxane) on three treatment schedules in patients with solid tumors. Cancer ChemotherPharmacol. 60:759-66 (2007).
• 13) Blum JL, Savin MA, Edelman G, Pippen JE, Robert NJ, Geister BV, Kirby RL, Clawson A, O'Shaughnessy JA. Phase II study of weekly albumin-bound paclitaxel for patients with metastatic breast cancer heavily pretreated with taxanes. Clin Breast Cancer 7:850-6 (2007).
• 14) Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M. Gemcitabine Plus nab-Paclitaxel Is an Active Regimen in Patients With Advanced Pancreatic Cancer: A Phase I/II Trial. J ClinOncol. 29:4548-54 (2011).
• 15) Gamelin, E, Delva, R, Jacob, J, et al: “Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: Results of a multicenter randomized trial of patients with metastatic colorectal cancer.” J. Clin Oncol 13:2099-2105, 2008.