Technetium Tc 99m sulfur colloid phenotypic probe for the pharmacokinetics and pharmacodynamics of PEGylated liposomal doxorubicin in women with ovarian cancer.

PURPOSE: Significant variability in the pharmacokinetics and pharmacodynamics of PEGylated liposomal doxorubicin (PLD) exists. PLD undergoes clearance via the mononuclear phagocyte system (MPS). Technetium Tc 99m sulfur colloid (TSC) is approved for imaging MPS cells. We investigated TSC as a phenotypic probe of PLD pharmacokinetics and pharmacodynamics in women with epithelial ovarian cancer. METHODS: TSC 10 mCi IVP was administered and followed by dynamic planar and SPECT/CT imaging and blood pharmacokinetics sampling. PLD 30-40 mg/m(2) IV was administered with or without carboplatin, followed by plasma pharmacokinetics sampling. RESULTS: There was a linear relationship between TSC clearance and encapsulated doxorubicin clearance (R(2) = 0.61, p = 0.02), particularly in patients receiving PLD alone (R(2) = 0.81, p = 0.04). There was a positive relationship (ρ = 0.81, p = 0.01) between maximum grade palmar-plantar erythrodysesthesia toxicity developed and estimated encapsulated doxorubicin concentration in hands. CONCLUSIONS: TSC is a phenotypic probe for PLD pharmacokinetics and pharmacodynamics and may be used to individualize PLD therapy in ovarian cancer and for other nanoparticles in development.

Meta-analysis of inter-patient pharmacokinetic variability of liposomal and non-liposomal anticancer agents.

A meta-analysis was conducted to evaluate the inter-patient pharmacokinetic (PK) variability of liposomal and small molecule (SM) anticancer agents. Inter-patient PK variability of 9 liposomal and SM formulations of the same drug was evaluated. PK variability was measured as coefficient of variance (CV%) of area under the plasma concentration versus time curve (AUC) and the fold-difference between AUCmax and AUCmin (AUC range). CV% of AUC and AUC ranges were 2.7-fold (P<0.001) and 16.7-fold (P=0.13) greater, respectively, for liposomal compared with SM drugs. There was an inverse linear relationship between the clearance (CL) of liposomal agents and PK variability with a lower CL associated with greater PK variability (R(2)=0.39). PK variability of liposomal agents was greater when evaluated from 0-336 h compared with 0-24h. PK variability of liposomes is significantly greater than SM. The factors associated with the PK variability of liposomal agents need to be evaluated. FROM THE CLINICAL EDITOR: In this meta-analysis, the inter-patient pharmacokinetic variability of 9 liposomal and small molecule anti-cancer agents was studied. The authors determined that several parameters are in favor of the liposomal formulation; however, the PK variability of the formulation was higher compared with small molecule agents, the reason for which remains to be determined in future studies.

Clinical risk factors of PEGylated liposomal doxorubicin induced palmar plantar erythrodysesthesia in recurrent ovarian cancer patients.

INTRODUCTION: Studies have shown that body composition, age, gender, changes in monocyte count and repeated dosing alter pharmacokinetic properties of PEGylated liposomal doxorubicin (PLD). However, limited information exists regarding the clinical risk factors of ovarian cancer patients who develop palmar plantar erythrodysesthesia (PPE) while receiving PLD for cancer recurrence. METHODS: We conducted a retrospective cohort analysis of consecutive patients with recurrent ovarian and primary peritoneal cancer who were treated with PLD from 2005 to 2009. Clinical and pathologic data were abstracted from electronic medical records. Statistical analyses were performed using univariate and bivariate analyses, logistic regression, and log rank-tests. RESULTS: Twenty-three percent (31/133) of patients developed PPE. Age, body mass index (BMI), race, stage, and histology did not significantly differ between PPE and non-PPE patients. There was a possible trend for decreasing PPE with increasing body mass index (BMI) (24.5% of normal weight, 27.5% of overweight; 23.8% of obese class I; 13.3% of obese class II; and 0% of obese class III), though not statistically significant. The number of chemotherapy regimens prior to PLD, and the mean cycles of PLD received did not differ between patients with and without PPE. 77.4% of PPE cases occurred within the first 3 infusion cycles. PPE was not associated with time to progression. CONCLUSION: Nearly one-quarter of ovarian cancer patients receiving PLD will develop PPE. Further investigation of factors such as BMI associated with PPE may aid in patient selection for PLD, and future development of other nanoparticle and liposomal agents.

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 (R(2) = 0.43, P = 0.04) and ROS production (R(2) = 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.

A review of study designs and outcomes of phase I clinical studies of nanoparticle agents compared with small-molecule anticancer agents.

PURPOSE: Nanoparticles or carrier-mediated agents have been designed to prolong drug circulation time, increase tumor delivery, and improve therapeutic index compared to their small-molecule counterparts. The starting dose for phase I studies of small molecules and nanoparticles anticancer agents is based on the toxicity profile of the most sensitive species (e.g., rat or canine), but the optimal animal model for these studies of nanoparticles is unclear. The objective of this study was to evaluate the design, progression, and outcomes of phase I studies of nanoparticles compared with small-molecule anticancer agents. EXPERIMENTAL DESIGN: In preclinical studies, the maximum tolerated dose (MTD) in rats and dogs was evaluated for nanoparticles and their respective small molecules. In phase I clinical trials in patients with advanced solid tumors, the basis for starting dose, the number of dose escalations, number of patients enrolled, and the ratio of MTD to starting dose was determined for nanoparticles and small molecules. RESULTS: The mean ratio of MTD to starting dose in clinical phase I studies was significantly greater for nanoparticles (13.9 ± 10.8) compared with small molecules (2.1 ± 1.1; P = 0.005). The number of dose levels in a clinical phase I study was also significantly greater for nanoparticles (7.3 ± 2.9) compared with small molecules (4.1 ± 1.5; P = 0.008). CONCLUSIONS: The degree of dose escalation from starting dose to MTD was significantly greater for nanoparticles as compared with small-molecule anticancer drugs. These findings necessitate the need to identify the most appropriate preclinical animal model to use when evaluating nanoparticles toxicity.

Allometric scaling of pegylated liposomal anticancer drugs.

Pegylated liposomal formulations contain lipid conjugated to polyethylene glycol. The disposition of encapsulated drug is dictated by the composition of the liposome, thus altering the pharmacokinetic (PK) profile of the drug. Allometric scaling is based on a power-log relationship between body weight (W) and drug clearance (CL) among mammals and has been used to compare the disposition of nonliposomal drugs across species. The objectives of this study were to use allometric scaling to: (1) compare the disposition of pegylated liposomal drugs across speciesand determine the best scaling model and (2) predict PK parameters of pegylated liposomal drugs in humans. The PK of pegylated liposomal CKD-602 (S-CKD602), doxorubicin (Doxil®), and cisplatin (SPI-077) were compared. PK studies ofS-CKD602, Doxil®, and SPI-077 were performed at the maximum tolerated dose (MTD) in male and female mice, rats, dogs and patients with refractory solid tumors. The allometric equation used to evaluate the relationship between W and CL in each species was CL = a(W)(m) (a = empirical coefficient; m = allometric exponent). Substitution of physiological variables other than body weight, such as factors representative of the mononuclear phagocyte system (MPS) were evaluated. Dedrick Plots and Maximum Life-Span Potential (MLP) were used to determine scaling feasibility. Standard allometry demonstrated a relationship between clearance of S-CKD602, Doxil®, and SPI-077 and body, spleen, liver, and kidney weights, total monocyte count, and spleen and liver blood flow. However, using scaling to predict CL of these agents in humans often resulted in differences >30%. Despite a strong correlation between body weight and MPS-associated variables with CL among preclinical species, the use of the equations did not predict CL. Thus, new methods of allometric scaling and measures of MPS function need to be developed.

Prevention strategies for antimicrobial resistance: a systematic review of the literature.

Antibiotics offer great benefits by reducing the duration and severity of illnesses and aiding in infection transmission control. With this being said, the inexorable process of antimicrobial drug resistance is to some degree unavoidable. Although drug resistance will likely persist and is to be expected, the overall level can be dramatically decreased with increased attention to antibiotic overuse and the pharmacokinetic and pharmacodynamic properties of different drug formulations, and the use of proper hygiene and protective barriers. Implementation of such practices as microbial surveillance and prophylaxis has been shown to result in decreased hospital length of stay, health care costs and mortality due to drug-resistant infections. This review will summarize current progress in preventative techniques aimed at reducing the incidence of infection by antimicrobial-resistant bacteria and the emergence and spread of antimicrobial-resistant strains. By employing a variety of prevention strategies, including proper personal hygiene, prescreening for carrier status before hospital admission, disinfection of hospital rooms, and careful monitoring of antimicrobial prescribing, marked progress can be achieved in the control of drug-resistant pathogens, which can translate into more effective antimicrobial therapy.

An evidence-based elective on dietary supplements.

OBJECTIVE: To implement and evaluate the effectiveness of a pharmacy elective on dietary supplements that emphasized evidence-based care. DESIGN: A 3-credit elective that employed both traditional lectures and a variety of active-learning exercises was implemented. The course introduction provided a background in dietary supplement use and evidence-based medicine principles before addressing dietary supplements by primary indication. ASSESSMENT: Student learning was assessed through quizzes, case assignments, discussion board participation, and completion of a longitudinal group project. Precourse and postcourse surveys were conducted to assess students' opinions, knowledge, and skills related to course objectives. CONCLUSION: The course was an effective way to increase students' knowledge of dietary supplements and skills and confidence in providing patient care in this area.