So-called pharmacometrics were used for information creation and decision-making in the drug development and drug approval process. However, for individualized drug therapy in clinical settings, pharmacometrics were not fully utilized. Therefore, our research group has defined, as “clinical pharmacometrics”, clinical contribution to decision-making in individualized drug therapy, especially with dosage optimization support and adverse effects management, by pharmacist-led quantitative analysis, evaluation and prediction using mathematical statistical methods. We show here some examples of practicing clinical pharmacometrics. In the case of supporting meropenem dosage optimization, we developed a population pharmacokinetic model and then performed random simulation to predict the efficacy of dosages (the drug exposure time above the minimum inhibitory concentration) by employing a probabilistic approach considering the variation of the patient and bacteria. The optimized meropenem dosage achieved favorable outcome. In the case of managing adverse effects of voriconazole, we developed a population pharmacogenomic-pharmacokinetic model and a logistic pharmacodynamic model, and then performed simulation to predict the safety of dosages (the hepatotoxic effects). These results optimized the voriconazole dosage according to the body weight and CYP2C19 genotype of the patient, considering the hepatotoxicity probability. As in these examples, for optimal drug therapy in individual patients, pharmacists need to practice clinical pharmacometrics by repeating the cycle of processes: clinical data measurement in the medical setting, acquisition of quantitative pharmaceutical knowledge, and provision of therapeutic benefits to patients.
Preparation of an anticancer drug is usually conducted on a disposable medical sheet (work sheet) in order to reduce pollution in biological safety cabinets (BSCs). However, scattered anticancer drugs might adhere to infusion bags or bottle surfaces placed on these work sheets, and anticancer drug pollution may flow out of BSCs. We have developed a new work sheet incorporated with an adsorbent for anticancer drugs using activated carbon (active carbon sheet) to reduce the pollution outflow from the work sheets and evaluated the ability of the anticancer drug adsorption under experimental conditions.●Prepared solutions of seven anticancer drugs were spilled on the control work sheet and active carbon sheet, followed by placing the infusion bottle or bag on these sheets. The anticancer drug adhering to the infusion bottle or bag surface was collected by a wipe method and subsequently assayed. We then immersed these sheets in anticancer drug solutions and examined the adsorption ability.●The active carbon sheet had only traces of various anticancer drugs adhering to the infusion bottle or bag surface when compared to the control sheets. The concentrations of the anticancer drugs while the active carbon sheet was immersed in the drug solutions were less. The anticancer drug absorbency of the work sheet appears to be critical in preventing anticancer drug outflow from the BSCs to the preparation environment. Use of the new work sheet with active carbon might be beneficial in reducing anticancer drug pollution outflow during preparation.
The serum concentration of vancomycin (VCM) must be maintained above a minimum level to be therapeutically effective. However, it is difficult to achieve the optimum serum concentrations in patients undergoing continuous hemodiafiltration (CHDF) because of the change in the pharmacokinetics of administered drugs. To address this problem, we used the Sawchuk-Zaske method to examine the dosage required to achieve optimal VCM levels in patients undergoing CHDF. Blood samples were taken in the drug-elimination phase (5-6 h after administration, which is earlier than usual) to estimate the pharmacokinetics of VCM. The subjects were 11 patients who were administered VCM while undergoing CHDF in the intensive care unit between February 2010 and February 2015. Blood samples were collected at three different times: the first just before the administration of VCM, the second 2 h after VCM administration, and the third 5-6 h (group A) or 16-17 h (group B) after VCM administration. The VCM clearance was 35.6 ± 6.0 and 38.4 ± 4.9 mL/min in group A and B. The distribution volumes were 0.80 ± 0.12 and 0.93 ± 0.23 L/kg in groups A and B, respectively. No significant differences groups were found. Consequently, even if the final blood sample is taken relatively soon after drug administration (5-6 h), the estimated pharmacokinetic parameters can be used to adjust VCM dosage to achieve optimum serum concentrations. Because it is important to adjust the VCM dosage as quickly as possible, these findings should prove useful in clinical practice.
The anatomical therapeutic chemical/defined daily dose system (DDD), recommended by the World Health Organization, uses drug consumption data and calculates the density of antimicrobial agent use and is used at many institutions. The day of therapy (DOT) is an index used to evaluate the density of antimicrobial agent use based on the duration of use and is not related to the daily dose. We determined DDD and DOT semiannually from September 1, 2008, to March 31, 2014, and calculated the ratio of DDD to DOT (DDD / DOT). The DDD / DOT ratio can be used to evaluate the change of the daily dose. We then compared these values and evaluated their effect on the resistance ratio for Pseudomonas aeruginosa. Six drugs were evaluated in this study: ceftazidime, cefozopran, cefepim, imipenem/cilastatin, meropenem, and ciprofloxacin. All drugs, except ciprofloxacin, showed a significant difference between DDD and DOT. The resistance ratio for Pseudomonas aeruginosa was not statistically correlated with three indexes (DDD, DOT, and DDD / DOT). The three indexes (DDD, DOT, and DDD / DOT) can be used to examine the usage trends of antimicrobial agents. However, these three indicators did not show any correlation with the susceptibility rate. Therefore, these indexes should be used on the basis of their characteristics.
EBRANTIL® Capsules are a drug product of urapidil, an alpha-1 adrenergic receptor antagonist, in the form of enteric/sustained-release granule filled capsules. This product can be administered as a solution prepared by the simple suspension method (SSM) to patients with gastrostomy through tubes; however, there is no information on the elution behavior of the drug administered by SSM.
In this study, one EBRANTIL® Capsules 15 mg was put in 20 mL of purified water or Japanese Pharmacopoeia (JP) 1st fluid for the dissolution test (pH 1.2) of 55 and 37℃. The test container was left for 10 minutes, then the content was suspended. The dissolution test was carried out in JP 1st fluid.
The elution of urapidil from EBRANTIL® Capsules untreated by SSM was 30% or less in 60 minutes. Ninety percent or greater of urapidil eluted in 30 minutes treated with water of 55℃. The elution rate of urapidil treated with water of 37℃ was relatively slower than that; however, 60% or greater urapidil eluted in 60 minutes. The elution behavior of urapidil from the capsule treated with JP 1st fluid was almost the same as that of the untreated EBRANTIL® Capsules. These data suggest that the granules in the capsules were slightly dissolved in JP 1st fluid, but they dissolved immediately in water of 55 and 37℃.
In conclusion, EBRANTIL® Capsules should not be administered by SSM to avoid lowering blood pressure when treating patients.
Japan International Cooperation Agency dispatched two medical teams to Nepal in response to a request from its government following a 7.8 magnitude earthquake. The first Japan Disaster Relief (JDR) medical team consisted of 46 members and the second team consisted of 34 members, and each team included two pharmacists. The first team deployed an open-air hospital in Barhabise village, Sindhupalchok District, located northeast of Kathmandu, where medical needs were high. The pharmacists not only dispensed medicines but also selected and managed the pharmaceutical stock. Furthermore, they purchased midazolam, used in surgery at the field hospital, from the local pharmacy, and performed physical assessments for hospital admissions. The second medical team took over the field hospital from the first team on May 9; however, medical care was cancelled as a result of a 7.3 magnitude aftershock on May 12. Soon after the maximum aftershock, the second team treated patients in the village, and then moved to Kathmandu and gave medical assistance at Dhulikhel Hospital-Kathmandu University Hospital (DH-KUH). Here, the pharmacists assisted with sorting and organizing the medicines donated by various countries, as well as providing workshops for the DH-KUH nurses and community medicine personnel. Such activities indicated that to provide appropriate healthcare for victims, the pharmacist was also required to be a medical logistician.
Sulfamethoxazole / trimethoprim (ST) is the most effective prophylaxis and the first-line treatment for Pneumocystis jirovecii pneumonia (PCP). Adverse reactions such as rash or fever to ST are more frequent and severe in human immunodeficiency virus (HIV)-infected patients as compared to uninfected individuals. Intravenous pentamidine isethionate (PTM) is recommended for patients who cannot tolerate ST, and oral suspension of atovaquone (ATQ) is the third alternative agent. The most common adverse effects of alternative therapies include severe dysglycemia, diarrhea and leukopenia with PTM; and nausea, rash and headache with ATQ. Such reactions limit continuation of the treatment for PCP.
A 35-year-old HIV-infected female with PCP was given ST. She presented with systemic rash, fever, nausea and vomiting by ST. PTM was administered to her as an alternative agent. However, it was discontinued because of diarrhea, vomiting and leukopenia. Therefore, we gave her ATQ as the third alternative agent. However, it was discontinued because of systemic eruption with the itching. Although we resumed PTM, it was discontinued because of similar side effects to the initial administration. We chose ATQ that had fewer side effects than others, and tried desensitization. It was successful and secondary prophylaxis of PCP was also possible.
This case suggests a likelihood that desensitization to ATQ can be beneficial for the patients suffering from the treatment and prevention of HIV-related PCP by the adverse events due to ST, PTM and ATQ.