Clinic, PSC, Appalachian Regional Healthcare, Hazard, Kentucky STUDY OBJECTIVE To estimate vancomycin pharmacokinetic parameters and dosing requirements in a cohort of extremely obese patients. DESIGN Prospective pharmacokinetic study. SETTING Acute care community teaching hospital. PATIENTS Thirty-one extremely obese (body mass index [BMI] ≥ 40 kg/m 2 ) men and women who were receiving vancomycin for at least 3 days for suspected or confirmed Staphylococcus aureus infections. MEASUREMENTS AND MAIN RESULTS Population pharmacokinetic parameters were used to determine vancomycin doses that target trough concentrations of 10-20 lg/ml. Three serum vancomycin concentrations (peak, trough, and midpoint) were measured at steady state for each patient. A 24-hour urine collection was performed to determine creatinine clearance (Cl cr ). A one-compartment intravenous infusion model was fit to the serum vancomycin concentrations by using nonlinear mixedeffects modeling. Covariates that affect the volume of distribution and clearance of vancomycin were explored. Patients had a median weight of 147.9 kg, BMI of 49.5 kg/m 2 , and a Cockcroft-Gault Cl cr of 124.8 ml/minute/1.73 m 2 . Patients received a median vancomycin dose of 4000 mg/day that provided a median 24-hour area under the concentration-time curve (AUC) of 582.9 (interquartile range 513.8-726.2) mgÁhour/L. The population mean volume of distribution was 0.51 L/kg, and clearance was 6.54 L/hour. Simulations indicated that 4000-5000 mg/day of vancomycin provided ≥ 93% probability 24-hour AUC/minimum inhibitory concentration (MIC) ratio of ≥ 400 for an MIC of 1 lg/ml. CONCLUSION Total body weight and Cl cr influenced volume of distribution and vancomycin clearance, respectively. Vancomycin can be initiated in extremely obese patients at dosages determined based on renal function and pharmacokinetic parameter estimates from this study. Vancomycin serum concentrations should be monitored to ascertain attainment within the therapeutic range. KEY WORDS pharmacokinetics, vancomycin, peak, trough, obesity, NONMEM. Vancomycin is a tricyclic glycopeptide antibiotic that is useful in the treatment of serious staphylococcal and enterococcal infections. 1 Its pharmacokinetic profile has been described by one-, two-, or three-compartment models, 2-4 although the one-compartment model offers simplicity in clinical practice. Despite its hydrophilicity, vancomycin is widely distributed, with a volume of distribution ranging between 0.4 and 1 L/kg of total body weight. 2,5,6 After intravenous administration, renal elimination accounts for 80-90% of vancomycin clearance, 2,4,7

The apparent in vivo blood stability of AR-67 is partly dependent on the increased carboxylate clearance. This may have clinical implications for populations with single nucleotide polymorphisms that impair the function of uptake transporter genes (e.g., SLCO1B1), which are potentially responsible for AR-67 carboxylate clearance.

Absorption of AR-67 is likely affected by solubility of its lactone form and interaction with efflux pumps in the gut. AR-67 appears to be absorbed as the lactone form, most likely due to gastric pH favoring its formation and predominance. F increased at higher doses suggesting saturation of efflux mechanisms.

Pemetrexed (Alimta®) is a novel anti-folate antimetabolite agent that is used in combination with cisplatin for the treatment of patients with unresectable malignant pleural mesothelioma and as a single agent or in combination with cisplatin for patients with locally advanced or metastatic non-small-cell-lung-cancer. Cutaneous adverse reactions are common side effects of pemetrexed for which the manufacturer recommends 3-day premedication with dexamethasone 4 mg by mouth twice daily-(the day before, the day of, and the day after treatment). Patients' adherence to this premedication regimen is of concern. We report 14 cases of metastatic non-small-cell-lung-cancer patients who were premedicated with a single dose of dexamethasone 20 mg prior to pemetrexed or pemetrexed-based chemotherapy. None of these patients reported a grade 3 or above skin reactions over the course of their treatments. These findings suggest that a single dose of dexamethasone 20 mg may be an alternative premedication regimen in patients with metastatic non small cell lung cancer receiving pemetrexed or pemetrexed-based chemotherapy.