The drug removal rate during hemodialysis is an important factor in determining the dosage regimen for patients undergoing hemodialysis and the prospect of hemodialysis being used as an emergency treatment for drug intoxication. However, the data pertaining to drug removal rate during hemodialysis is limited. Although the drug removal rate during hemodialysis should be defined as the rate of actual removal of drug from the body by hemodialysis, it is sometimes defined as the rate of extraction of drug by dialyzer or the rate of change in plasma drug concentration before and after hemodialysis. These estimation methods may cause errors in clinical trial assessments as they do not consider the volume of distribution (V_d) or post-dialytic redistribution. Of the factors influencing drug removal by hemodialysis, molecular weight exerts a minor effect as evidenced by drugs with large molecular weight such as protein drugs not being removed by hemodialysis, while protein binding and V_d exerts a major effect, especially for drugs with low to medium molecular weight. We have previously reported a highly accurate equation for the prediction of drug removal rate during hemodialysis in clinical practice. This equation incorporates the unchanged drug fraction excreted into the urine (fe) as a factor influencing drug removal by hemodialysis. The exceptions for the accurate prediction of drug removal by this equation are drugs for which tubular secretion and reabsorption contribute significantly to fe. Hemodialysis conditions, such as blood flow rate, hemodialysis duration, and dialysis membrane may affect the actual drug removal rate during hemodialysis in clinical practice. Therefore, it is recommended that the predicted value of this equation be adjusted when designing a drug dosage regimen for patients undergoing hemodialysis and should take into consideration hemodialysis conditions and pharmacokinetic changes in patient for obtaining an individualized estimation of drug removal rate during hemodialysis. In this review, we will discuss the issues arising from the methods used to assess drug removal rate during hemodialysis, the factors that influence drug removal by hemodialysis, and the equation for predicting drug removal rate during hemodialysis.

In patients with severe renal dysfunction, the dose of drugs administered may be overdose or underdose; therefore, proper use of the prescription could be optimized by introducing a system (renal function check) that evaluates renal function and dosage at the time of drug administration. We aimed to examine the extent to which the optimization progressed by performing a renal function check in patients with severe renal dysfunction and investigate the effect of the renal function check. Among the drugs subjected to renal function check in our hospital, sitagliptin tablets, levofloxacin tablets, and famotidine tablets/powder, which were the most prescribed, were compared between the prescription before and after the introduction of the renal function check. Five items were mainly examined: the number of prescriptions, appropriate usage rate in dialysis patients, appropriate usage rate in non-dialysis patients, overdose rate, and underdose rate.

This study revealed that the introduction of renal function checks led to the optimization of prescriptions. However, challenges were encountered with some drugs. Sitagliptin was used as a brought-in drug in an outpatient setting and sometimes continued during hospitalization, leading to an overdose. The loading dose of levofloxacin was not prescribed and tended to cause an underdose. Therefore, the following improvement plans were considered. If there is an instruction to continue the brought-in drug, it is considered that the pharmacist can prevent an overdose by proactively prescribing the brought-in drug. In addition, by promoting cooperation among hospitals and community pharmacies/pharmacists,such as utilization CKD stickers,it can be expected that the overdose of brought-in drugs will further be suppressed. It is considered that the prescription of underdosed drugs will be optimized by the pharmacist changing the prescription. However, it is necessary to consult with the doctor in advance before the pharmacist prescribes. Furthermore, by going through protocol-based pharmacotherapy management, the prescription can be optimized, and doctors’ work can be reduced by task shifting.

Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors are a new class of treatment for renal anemia, a complication of chronic kidney disease. Despite the clinical significance of these inhibitors, there are insufficient data on their side effects. Moreover, the effect of HIF-PH inhibitors on thyroid function is not clear due to conflicting findings. Certain reports have indicated that thyroid-stimulating hormone (TSH) is reduced by roxadustat, while others associate hypothyroidism with daprodustat. In this study, we accordingly investigated the effects of roxadustat and daprodustat on TSH level. We conducted a retrospective study monitoring TSH level changes in patients on maintenance hemodialysis who were presented with either roxadustat or daprodustat at Rakuwakai Otowa Kinen Hospital, from February 2021 to July 2021. The patients included in this study were those whose TSH level had been within reference range 210 days before treatment with the drug, and whose TSH level was again measured after the administration of the drug. A TSH decrease to below the reference level was observed in 8 of 9 patients in the roxadustat group and in 1 of 12 patients in the daprodustat group. Changes in TSH level before and after treatment were -2.009 μIU/mL (95% CI = -3.181 to -0.837 μIU/mL; P = 0.004) and +0.086 μIU/mL (95% CI = -0.560 to 0.732 μIU/mL; P = 0.775), respectively. Two patients in the roxadustat group had TSH levels significantly reduced to less than 1/10 of the lower limit of the reference value. Additionally, two patients in the roxadustat group changed their treatment to daprodustat in the course of the study, and the TSH levels of both patients improved to within the reference value after 13 and 15 days. It is thus necessary to monitor TSH levels because roxadustat greatly reduces TSH levels to less than 1/10 of the lower limit of the reference range. This study suggests that TSH reduction is a drug-specific effect, and shows the possibility to continue treatment for renal anemia by changing the treatment to a different HIF-PH inhibitor.

Cyclosporin A (CyA) is often used to treat patients with steroid resistance and steroid dependence, which are indicative of recurrent-nephrotic syndrome. However, there are only a few detailed reports on the optimal dosing frequency of CyA. Therefore, in this study, we investigated the safety and efficacy of once- versus twice-daily dosing of CyA in patients with nephrotic syndrome.

Our study included patients who received CyA therapy from January 1, 2011, to September 30, 2017; had area under the plasma concentration-time curve values calculated for 0-4 hours; and continued CyA treatment for more than six months. Thirty-nine patients were included in this study (26 patients dosed once-daily; 13 patients dosed twice-daily). We used the change in the urine protein-to-creatinine ratio between six months after the initiation of CyA therapy as an effective index. At six months, the index was significantly lower in patients who were receiving once-daily dose than those receiving twice-daily CyA (75.19 ± 20.76 mg vs 103.85 ± 30.22 mg, P<0.01). Additionally, there was no significant difference in once-daily dosing and twice-daily dosing (69.2% vs. 53.8%, p=0.48). Notably, at 6 months, the laboratory data for both once- and twice-daily dosing were within the normal range.

Overall our results show that once-daily dosing of CyA is, at least as effective as twice-daily dosing. Importantly, once-daily dosing enhances patient compliance, expenditure, and ensures patient safety; therefore, our results encourage the use of once-daily dosing of CyA in clinics.