Parag Kumar

Interpatient pharmacokinetic and pharmacodynamic variability of carrier-mediated anticancer agents

Major advances in the field of carrier‐mediated agents (CMAs) have revolutionized drug delivery capabilities over the past decade. While providing numerous advantages over their small‐molecule counterparts (solubility, duration of exposure, and delivery to the site of action are higher), these agents display substantial variability in systemic clearance (CL) and distribution, tumor delivery, and pharmacologic effects. This review provides an overview of factors that affect the pharmacokinetics (PK) and pharmacodynamics (PD) of CMAs in preclinical models and patients.

Translational Studies of Phenotypic Probes for the Mononuclear Phagocyte System and Liposomal Pharmacology

As nanoparticles (NPs) are cleared via phagocytes of the mononuclear phagocyte system (MPS), we hypothesized that the function of circulating monocytes and dendritic cells (MO/DC) in blood can predict NP clearance (CL). We measured MO/DC phagocytosis and reactive oxygen species (ROS) production in mice, rats, dogs, and patients with refractory solid tumors. Pharmacokinetic studies of polyethylene glycol (PEG)-encapsulated liposomal doxorubicin (PEGylated liposomal doxirubicin [PLD]), CKD-602 (S-CKD602), and cisplatin (SPI-077) were performed at the maximum tolerated dose. MO/DC function was also evaluated in patients with recurrent epithelial ovarian cancer (EOC) administered PLD. Across species, a positive association was observed between cell function and CL of PEGylated liposomes. In patients with EOC, associations were observed between PLD CL and phagocytosis (R2 = 0.43, P = 0.04) and ROS production (R2 = 0.61, P = 0.008) in blood MO/DC. These findings suggest that probes of MPS function may help predict PEGylated liposome CL across species and PLD CL in patients with EOC.

Antiretroviral Boosting Agent Cobicistat Increases the Pharmacokinetic Exposure and Anticoagulant Effect of Dabigatran in HIV-Negative Healthy Volunteers

Drug interactions between antiretroviral therapy and anticoagulant medications are of particular concern given that ≈50% of the current HIV population is >50 years of age. Moreover, HIV infection is characterized by a hypercoaguable state and premature immunologic aging, in which thromboembolic events may be as much as 10 times more prevalent than in the general population across all age spectra.1 Dabigatran was the first direct oral anticoagulant approved by the US Food & Drug Administration and is the only direct oral anticoagulant with a US Food & Drug Administration -approved specific reversal agent, idarucizumab. Unlike warfarin and many other direct oral anticoagulants, dabigatran is not a substrate, inhibitor, or inducer of cytochrome P450 metabolic enzymes. However, dabigatran is a substrate of Permeability-glycoprotein (P-gp) and renal multidrug and toxin extrusion-1 transporters. Cobicistat is a US Food & Drug Administration -approved antiretroviral-boosting agent that is coformulated with numerous fixed-dose combination antiretroviral products because of its inhibitory effects on cytochrome P450 3A4. Currently, ≈40% of all treatment-naive patients with HIV in the United States are initiated on a cobicistat-boosted antiretroviral regimen. In addition to cytochrome P450 3A4, cobicistat is also an inhibitor of both P-gp and multidrug and toxin extrusion-1 transporters.2 Thus, this study aimed to determine whether the …

Pharmacokinetics, Pharmacodynamics, and Proposed Dosing of the Oral JAK1 and JAK2 Inhibitor Baricitinib in Pediatric and Young Adult CANDLE and SAVI Patients

Population pharmacokinetic (popPK) modeling was used to characterize the PK profile of the oral Janus kinase (JAK)1/JAK2 inhibitor, baricitinib, in 18 patients with Mendelian interferonopathies who are enrolled in a compassionate use program. Patients received doses between 0.1 to 17 mg per day. Covariates of weight and renal function significantly influenced volume‐of‐distribution and clearance, respectively. The half‐life of baricitinib in patients less than 40 kg was substantially shorter than in adult populations, requiring the need for dosing up to 4 times daily. On therapeutic doses, the mean area‐under‐the‐concentration‐vs.‐time curve was 2,388 nM*hr, which is 1.83‐fold higher than mean baricitinib exposures in adult patients with rheumatoid arthritis receiving doses of 4 mg once‐daily. Dose‐dependent decreases in interferon (IFN) biomarkers confirmed an in vivo effect of baricitinib on type‐1 IFN signaling. PopPK and pharmacodynamic data support a proposal for a weight‐ and estimated glomerular filtration rate‐based dosing regimen in guiding baricitinib dosing in patients with rare interferonopathies.

Abstract 2673: Relationship between serum hormone levels and pharmacokinetics (PK) of PEGylated liposomal doxorubicin (PLD) in patients with refractory ovarian cancer

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Background: Pharmacokinetics (PK) of nanoparticle agents, such as PEGylated liposomes, are dependent upon the carrier and not the encapsulated drug. Previous studies have demonstrated a high degree of interpatient variability in the PK of PEGylated liposomal doxorubicin (PLD). We have previously demonstrated that circulating monocytes play a major role in clearance (CL) of PEGylated liposomes in patients. Estrogen and testosterone, which are largely secreted via the gonads, have been shown to modulate monocyte function and chemotaxis. In addition, estrone is converted from other steroid hormones in adipose tissue. Thus, we evaluated the relationship between serum hormone concentrations in blood samples and PK of PLD in patients with refractory ovarian cancer. Methods: PLD was administered at 30 or 40mg/m2 IV every 28 days with or without concurrent carboplatin at an AUC = 5 in patients (n = 10) with recurrent ovarian cancer. All patients had undergone bilateral salpingo-oophorectomy (BSO). Serial PK samples were obtained from time 0 h to 168 h and day 28 post PLD dose. Plasma was processed to measure encapsulated and released doxorubicin using solid phase separation and HPLC with fluorescence detection. CL of encapsulated doxorubicin in plasma was calculated by non-compartmental methods. Prior to administration of PLD, serum samples were collected and concentrations of estrone, estrogen, testosterone, and dihydrotestosterone were measured. Results: There was a direct linear relationship between encapsulated doxorubicin CL and both testosterone (R2 = 0.72) and estrone concentrations (R2 = 0.54) in all patients. When patients were subdivided based on PLD monotherapy (n = 6) or PLD + carboplatin (n = 4), there was a stronger relationship between encapsulated doxorubicin CL and both testosterone (R2 = 0.88) and estrone concentrations (R2 = 0.86) in patients receiving PLD monotherapy. Estrogen and dihydrotestosterone concentrations were below quantification limits for the majority of patients and thus were not evaluated. There was no relationship between patient body weight and BMI and estrone concentrations (R2 = 0.25 and R2 = 0.13 respectively). Conclusions: These findings indicate that serum hormone concentrations are associated with encapsulated doxorubicin CL and thus may be useful for individualizing PLD therapy in patients with ovarian cancer and other malignancies. Patient body weight and BMI were not associated with estrone concentrations in patients with ovarian cancer, suggesting phenotypic and/or genotypic differences in estrone production in adipose tissue. Low estrogen concentrations are consistent with the patients undergoing BSO surgery as standard treatment of ovarian cancer. The relationship between hormone levels and PK of nanoparticles needs to be further evaluated as a method to individualize nanoparticle therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2673. doi:1538-7445.AM2012-2673

Mononuclear phagocyte system function and nanoparticle pharmacology in obese and normal weight ovarian and endometrial cancer patients

PurposeObesity may alter mononuclear phagocyte system (MPS) function and the pharmacology and efficacy of nanoparticles therapies, such as PEGylated liposomal doxorubicin (PLD). We aimed to evaluate the relationships between hormone and chemokine mediators of MPS function and the pharmacokinetic (PK) exposure of PLD in obese and normal weight patients with ovarian and endometrial cancer.MethodsHormone and chemokine mediators in obese and normal weight ovarian and endometrial cancer patients were measured. A separate pharmacology study was performed that evaluated the relationship between serum hormone concentrations, MPS function, and PK disposition of PLD in refractory ovarian cancer patients.ResultsUnivariate analysis revealed a significant relationship between serum estradiol and body mass index (OR 8.64, 95% CI 2.67–28.0, p < 0.001). Estrone and testosterone concentrations were positively correlated with MPS function (ρ = 0.57 and 0.53, p = 0.14 and 0.18, respectively) and inversely correlated with PLD PK exposure (ρ = − 0.75 and − 0.76, respectively, p = 0.02 for both).ConclusionsHigher MPS function resulting in reduced PLD exposure is a potential mechanism for reduced efficacy of PLD and other nanoparticles observed in obese patients with cancer. PK simulations suggest higher doses of PLD are required in obese patients to achieve similar exposures as standard dosing in normal weight patients.

Abstract 750: Impairment of clofarabine (CLO) clearance (CL) in the presence of cimetidine: Evidence of a drug-drug interaction between clofarabine and inhibitors of human organic cation transporter-2 (hOCT2)

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Background: CLO is a nucleoside analog with efficacy in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Preclinical studies using an isolated, perfused rat-kidney model suggested that CLO may be a substrate of OCT2, a channel that mediates the transport of cations across the renal tubular basolateral membrane. Evidence of this mechanism is lacking in humans, though this property could contribute to drug interactions with compounds such as cimetidine that inhibit hOCT2. Methods: Eligible patients were: 1) untreated AML ≤ 60 years of age unsuited for intensive induction therapies, 2) relapsed or refractory AML, or 3) MDS patients who failed ≤ 1 prior regimen. Patients were treated with CLO according to the schedule: CLO 15 mg/m2 IV day 1, CLO 30 mg/m2 PO day 3, CLO 15 mg/m2 IV day 5 preceded by two doses of oral cimetidine (800 mg PO 8-10 hours apart), and CLO 30 mg/m2 PO on days 6 and 7. Pharmacokinetic (PK) studies were obtained after CLO dosing on days 1, 3 and 5. CLO plasma concentration was determined, and concentration-time data was analyzed by non-compartmental methods. Oral bioavailability (F) was determined for each patient. The geometric means of area under the curve, 0-infinity (AUC), and CL for intravenous CLO administered after cimetidine doses were compared with AUC and CL for intravenous CLO administered without cimetidine. Results: To date, 8 patients have been treated. Mean F = 0.66, 90% confidence interval (CI) (0.49, 0.87). Comparisons of PK parameters between IV dosing with and without cimetidine are shown in the table. Conclusions: Co-administration of the hOCT2 inhibitor cimetidine with CLO appears to increase CLO AUC by impairing renal CL. Enrollment continues in an attempt to further support the putative mechanism of CLO renal clearance by hOCT2-mediated tubular secretion, and to further investigate the clinical import of this drug-drug interaction. ![Figure][1] Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 750. doi:1538-7445.AM2012-750 [1]: pending:yes