Vancomycin Pharmacokinetics Throughout Life: Results from a Pooled Population Analysis and Evaluation of Current Dosing Recommendations.

BACKGROUND AND OBJECTIVES: Uncertainty exists regarding the optimal dosing regimen for vancomycin in different patient populations, leading to a plethora of subgroup-specific pharmacokinetic models and derived dosing regimens. We aimed to investigate whether a single model for vancomycin could be developed based on a broad dataset covering the extremes of patient characteristics. Furthermore, as a benchmark for current dosing recommendations, we evaluated and optimised the expected vancomycin exposure throughout life and for specific patient subgroups. METHODS: A pooled population-pharmacokinetic model was built in NONMEM based on data from 14 different studies in different patient populations. Steady-state exposure was simulated and compared across patient subgroups for two US Food and Drug Administration/European Medicines Agency-approved drug labels and optimised doses were derived. RESULTS: The final model uses postmenstrual age, weight and serum creatinine as covariates. A 35-year-old, 70-kg patient with a serum creatinine level of 0.83 mg dL-1 (73.4 µmol L-1) has a V1, V2, CL and Q2 of 42.9 L, 41.7 L, 4.10 L h-1 and 3.22 L h-1. Clearance matures with age, reaching 50% of the maximal value (5.31 L h-1 70 kg-1) at 46.4 weeks postmenstrual age then declines with age to 50% at 61.6 years. Current dosing guidelines failed to achieve satisfactory steady-state exposure across patient subgroups. After optimisation, increased doses for the Food and Drug Administration label achieve consistent target attainment with minimal (± 20%) risk of under- and over-dosing across patient subgroups. CONCLUSIONS: A population model was developed that is useful for further development of age and kidney function-stratified dosing regimens of vancomycin and for individualisation of treatment through therapeutic drug monitoring and Bayesian forecasting.

Single-dose dexamethasone for the prevention of pemetrexed associated cutaneous adverse reactions.

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.

Pharmacokinetics of vancomycin in extremely obese patients with suspected or confirmed Staphylococcus aureus infections.

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 µg/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 (Clcr ). A one-compartment intravenous infusion model was fit to the serum vancomycin concentrations by using nonlinear mixed-effects 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 Clcr 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) mg·hour/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 µg/ml. CONCLUSION: Total body weight and Clcr 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.

Evaluation of a Pharmacist-Managed Heart Failure Education Project: Empowering Patients to Self-Manage Their Disease.

Background: Recent reimbursement cuts for hospitals with higher 30-day heart failure (HF)-related readmission rates call for means of reducing those readmissions. Objective: To determine if pharmacist-initiated education increases HF knowledge and assess if an increase in HF knowledge decreases HF readmission. Methods: This was a prospective interventional study. Participants were ≥18 years old admitted through the emergency department of a 322-bed community hospital with a diagnosis and/or past medical history of HF. Terminal/palliative care patients, patients residing in an assisted-living environment, or patients with a mental illness that deemed them incapable of participating were excluded. Forty-eight patients received pharmacist-initiated HF education on HF pathophysiology and its pharmacologic and nonpharmacologic treatment. Medication assistance and ancillary services were consulted when necessary. Patients' knowledge of HF was assessed using the same questionnaire prior to education and through a follow-up phone call within 7 days postdischarge. Results: Posteducation HF knowledge scores were 13.7 points higher than preeducation scores (P < .05). Twenty-five patients (52%) had HF as a primary discharge diagnosis. Of those patients, 9 (36%) were readmitted within 30 days for any cause. Only 3 patients (12%) had a HF-related diagnosis at readmission. There was a statistical difference in the level of knowledge but that was not translated into a statistical difference in readmission rates. Conclusion: Patients' HF knowledge scores increased after pharmacist education. Improvements in HF knowledge could not be correlated with readmission rates. However, the majority of HF patients in this study did not have a HF-related diagnosis at the time of readmission.

Protracted dosing of the lipophilic camptothecin analogue AR-67 in non-small cell lung cancer xenografts and humans.

PURPOSE: Although preclinical studies on camptothecin antitumor effect have demonstrated the superiority of low-dose protracted dosing, these findings were not replicated in the clinic. 7-t-butyldimethylsilyl-10-hydroxycamptothecin (AR-67) is a camptothecin analogue currently under investigation in early phase clinical trials. To maximize the therapeutic potential of AR-67, we sought to identify factors that affect response to treatment. METHODS: After determining the maximum tolerated dose using neutropenia as a toxicity endpoint, xenografts received AR-67 under varying dosing schedules and were monitored for survival. On the last treatment day, tumor tissue was collected and topoisomerase 1 (Top1), γH2AX, caspase 3 and PARP protein content was evaluated. AR-67 plasma and tumor pharmacokinetics were also studied in mice and cancer patients who were administered AR-67 as a 1-h intravenous infusion on days 1, 4, 8, 12 and 15 every 21 days. RESULTS: Low-dose protracted dosing schedules increased animal survival compared to less frequent, but higher-dose courses and the expression of Top1 and γH2AX were schedule dependent. Fatigue and neutropenia were the dose-limiting toxicities identified in patients receiving AR-67. Finally, elimination of AR-67 from the tumor site was slower in both xenografts and tumor of a patient enrolled in the pilot clinical trial. CONCLUSIONS: We demonstrated that low-dose protracted dosing schedules of AR-67 are therapeutically effective and Top1 reflects the biological activity of AR-67 in xenografts. Moreover, the tumor pharmacokinetics as well as the efficacy and safety of AR-67 given intermittently to cancer patients warrant further investigation.

The effect of breast cancer resistance protein, multidrug resistant protein 1, and organic anion-transporting polypeptide 1B3 on the antitumor efficacy of the lipophilic camptothecin 7-t-butyldimethylsilyl-10-hydroxycamptothecin (AR-67) in vitro.

AR-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin) is a lipophilic camptothecin analog, currently under early stage clinical trials. Transporters are known to have an impact on the disposition of camptothecins and on the response to chemotherapeutics in general due to their expression in tumor tissues. Therefore, we investigated the interplay between the breast cancer resistance protein (BCRP), multidrug resistant protein 1 (MDR1), and organic anion-transporting polypeptide (OATP) 1B1/1B3 transporters and AR-67 and their impact on the toxicity profile of AR-67. Using cell lines expressing the aforementioned transporters, we showed that the lipophilic AR-67 lactone form is a substrate for efflux transporters BCRP and MDR1. Additionally, OATP1B1 and OATP1B3 facilitated the uptake of AR-67 carboxylate in SLCO1B1- and SLCO1B3-transfected cell systems compared with the mock-transfected ones. Notably, both BCRP and MDR1 conferred resistance to AR-67 lactone. Prompted by recent studies showing increased OATP1B3 expression in certain cancer types, we investigated the effect of OATP1B3 expression on cell viability after exposure to AR-67 carboxylate. OATP1B3-expressing cells had increased carboxylate uptake as compared with mock-transfected cells but were not sensitized because the intracellular amount of lactone was 50-fold higher than that of carboxylate and comparable between OATP1B3-expressing and OATP1B3-nonexpressing cells. In conclusion, BCRP- and MDR1-mediated efflux of AR-67 lactone confers resistance to AR-67, but OATP1B3-mediated uptake of the AR-67 carboxylate does not sensitize OATP1B3-expressing tumor cells.

Pharmacokinetic modeling to assess factors affecting the oral bioavailability of the lactone and carboxylate forms of the lipophilic camptothecin analogue AR-67 in rats.

PURPOSE: Camptothecin analogues are anticancer drugs effective when dosed in protracted schedules. Such treatment is best suited for oral formulations. AR-67 is a novel lipophilic analogue with potent efficacy in preclinical models. Here we assessed factors that may influence its oral bioavailability in rats. METHODS: Plasma pharmacokinetic (PK) studies were conducted following administration of AR-67 lactone or carboxylate doses alone or after pre-dosing with inhibitors of the efflux transporters P-gp and Bcrp. A population PK model that simultaneously fitted to oral and intravenous data was used to estimate the bioavailability (F) and clearance of AR-67. RESULTS: An inverse Gaussian function was used as the oral input into the model and provided the best fits. Covariate analysis showed that the bioavailability of the lactone, but not its clearance, was dose dependent. Consistent with this observation, the bioavailability of AR-67 increased when animals were pretreated orally with GF120918 or Zosuquidar. CONCLUSION: 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.

Factors affecting the in vivo lactone stability and systemic clearance of the lipophilic camptothecin analogue AR-67.

PURPOSE: The narrow efficacy-toxicity window of anticancer agents necessitates understanding of factors contributing to their disposition. This is especially true for camptothecins as they exist in the lactone and carboxylate forms with each moiety differentially interacting with efflux or uptake transporters. Here we determined the disposition of the lactone and carboxylate forms of AR-67, a 3(rd) generation camptothecin analogue. METHODS: Pharmacokinetic studies were conducted in rats given intravenous boluses of AR-67 lactone or carboxylate with or without pharmacologic inhibitor pretreatment (GF120918 or rifampin). Pharmacokinetic modeling was used to estimate clearances, while simulations assessed the impact of clearance changes on overall AR-67 exposure. RESULTS: Our modeling showed that carboxylate clearance was 3.5-fold higher than that of the lactone. GF120918 decreased lactone clearance only, but rifampin decreased both lactone and carboxylate clearances. Simulations showed that decreasing carboxylate clearance, which controls the overall drug disposition, leads to significant increase in AR-67 exposure. CONCLUSION: 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.