The potential public health impact of the respiratory syncytial virus prefusion F protein vaccine in people aged ≥60 years in Japan: results of a Markov model analysis.

BACKGROUND: Respiratory syncytial virus (RSV), a common respiratory pathogen, can lead to severe symptoms, especially in older adults (OA). A recently developed RSV prefusion F protein (RSVPreF3 OA) vaccine confers high protection against RSV lower respiratory tract disease (LRTD) over two full RSV seasons. The aim of this study was to assess the potential public health impact of RSVPreF3 OA vaccination in the Japanese OA population. RESEARCH DESIGN AND METHODS: A static Markov model was used to estimate the number of symptomatic RSV cases, hospitalizations and deaths in the Japanese population aged ≥ 60 years over a 3-year time horizon. Japan-specific RSV epidemiology and healthcare resource use parameters were used; vaccine efficacy was derived from a phase 3 randomized study (AReSVi-006, NCT04886596). Vaccination coverage was set to 50%. RESULTS: Without vaccination, >5 million RSV acute respiratory illness (ARI) would occur (2.5 million LRTD and 2.8 million upper respiratory tract infections) leading to ~ 3.5 million outpatient visits, >534,000 hospitalizations and ~ 25,500 RSV-related deaths over 3 years. Vaccination could prevent > 1 million RSV-ARI cases, 728,000 outpatient visits, 143,000 hospitalizations and 6,840 RSV-related deaths. CONCLUSIONS: RSVPreF3 OA vaccination is projected to have a substantial public health impact by reducing RSV-related morbidity and mortality in the OA population.

Respiratory syncytial virus (RSV) is one of the most frequent disease-causing agents that leads to common cold symptoms. In older adults, infection with RSV can result in severe complications including bronchitis/bronchiolitis, lung infection (pneumonia) and in rare cases death. Older people and people with chronic heart or lung disease are more likely to experience complications. We estimated that more than 5 million RSV cases occur in older adults (≥60 years) over a three-year period (1.8 million over one year). Many older adults (≥60 years) will see their treating physician because of an acute RSV infection or will be hospitalized.Recently, a vaccine has been registered which protects older adults against RSV disease: the RSV prefusion F protein Older Adult (RSVPreF3 OA) vaccine. Vaccination with RSVPreF3 OA could prevent RSV infection in the older adult population and reduce the number of outpatient visits and hospitalizations; the impact is particularly high in Japan, where 35% of people are 60 years or older. We used a public health impact model to estimate how many RSV cases, hospitalizations and deaths could be prevented if 50% of people aged ≥ 60 years received the RSVPreF3 OA vaccine: We found that the vaccine could prevent about 1 million RSV infections, more than 728,000 outpatient visits, approximately 143,000 hospitalizations and 6,840 RSV-related deaths over a three-year period.Adding RSVPreF3 OA vaccine to the national immunization program in Japan could protect older adults against RSV disease and reduce the burden on patients and the healthcare system.

Case of Pilomatricoma After Coronavirus Disease 2019 Vaccination.

The coronavirus disease 2019 (COVID-19), which is an infection caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), spread worldwide including Japan. This COVID-19 pandemic has changed the way of life around the world. To prevent the spread of infection, several COVID-19 vaccines were rapidly developed and their vaccination is recommended. While safety and effectiveness of these vaccines have been shown, various adverse reactions occur with a certain frequency. Pilomatricoma is a benign subcutaneous tumor. Cause of pilomatricoma is unclear, however, an external insult could be a cause of part of pilomatricoma. Herein, we report a rare case of pilomatricoma after COVID-19 vaccination. Pilomatricoma should be included in the differential diagnoses of nodular lesions arising after vaccination sites, including the COVID-19 vaccine.

Cost-Effectiveness Analysis Update of the Adjuvanted Recombinant Zoster Vaccine in Japanese Older Adults.

INTRODUCTION: This study aimed to update cost-effectiveness and public health impact estimates of the two-dose recombinant zoster vaccine (RZV) compared with no vaccination against herpes zoster (HZ) in the Japanese population aged 65 years. List price of the vaccine and latest RZV efficacy and waning estimates were incorporated. METHODS: A multicohort static Markov model with a cycle length of 1 year was used to follow a hypothetical cohort of one million people aged 65 years over their remaining lifetime (base case). Age-stratified vaccine efficacy and waning rates were updated on the basis of the latest clinical trial data (interim ZOE-LTFU; NCT02723773). First-dose coverage was assumed at 40%, and second-dose compliance was assumed at 95%. Costs and outcomes were discounted at 2% annually, and the incremental cost-effectiveness ratio (ICER) was calculated from payer and societal perspectives. The societal perspective considered productivity loss due to suffering HZ, or due to suffering HZ and time required for vaccination. Sensitivity analyses explored the overall uncertainties in the model. Scenario analyses for Japanese adults aged 50, 60, 70, 80, ≥ 50, and ≥ 65 years (main scenario) were conducted. An ICER below ¥5-6 million/quality-adjusted life-year (QALY) was considered cost-effective. RESULTS: RZV was estimated to prevent 71,423 HZ cases and 15,858 post-herpetic neuralgia (PHN) cases per million people aged 65 years compared with no vaccine in Japan. The ICER was ¥4,205,515 from a payer perspective and was most sensitive to assumptions regarding vaccine efficacy waning, proportion of patients with HZ developing PHN, and HZ incidence. From societal perspectives, ICERs were ¥3,854,192 (productivity loss from suffering HZ only) and ¥4,622,212 (productivity loss from suffering HZ and time required for vaccination). Overall, the results were considered robust under extensive sensitivity and scenario analyses. CONCLUSION: Vaccination against HZ with RZV is cost-effective compared with no vaccination in Japanese adults aged 65 years.

Deep Vein Thrombosis in Severe Motor and Intellectual Disabilities Patients and Its Treatment by Anticoagulants of Warfarin Versus Edoxaban.

Objective: Patients with severe motor and intellectual disabilities (SMID) often develop complications, including paralysis of the extremities due to abnormal muscular tonicity. Furthermore, the incidence of sudden death, which may be caused by pulmonary thromboembolism (PTE), is approximately 4.2%. Deep vein thrombosis (DVT) is attracting attention as an embolic source. In this study, DVT was confirmed in SMID patients by lower extremity venous ultrasound. The oral anticoagulant, warfarin, and novel oral anticoagulant, edoxaban tosilate hydrate, were administered, and their efficacies and safeties were evaluated. Materials and Methods: DVT patients were randomly allocated to warfarin and edoxaban groups. The frequency of hemorrhagic events and incidence of adverse events were investigated to evaluate efficacy and safety. Results: DVT was detected in 14 (8.4%) out of 167 patients. Four (0.067/person-month) hemorrhagic events occurred in the warfarin group from subcutaneous hemorrhage due to bruises caused by postural changes. Three (0.042/person-month) events occurred in the edoxaban group due to nasal hemorrhage caused by tracheal aspiration. There was no significant difference (p=0.5383) between groups. Conclusion: No significant differences were observed in hemorrhagic events between SMID patients with DVT treated with warfarin and edoxaban.

Cost-Effectiveness of the Adjuvant Recombinant Zoster Vaccine in Japanese Adults Aged 65 Years and Older.

INTRODUCTION: The incidence of herpes zoster (HZ) rises steeply after the age of 50 years and the number of HZ cases and complications such as postherpetic neuralgia (PHN) is predicted to increase because of the ageing population. The objective of this study was to estimate the cost-effectiveness of recombinant zoster vaccine (RZV) compared with no vaccine for the Japanese population aged ≥ 65 years. METHODS: A multi-cohort static Markov model with a cycle length of 1 year was used to follow a hypothetical cohort of 1 million people aged ≥ 65 years over their remaining lifetime. Vaccination at ≥ 65 years was used in alignment with the influenza and pneumococcal vaccines recommended from 65 years. Japan-specific data inputs for the model were obtained from local data sources. Age-stratified vaccine efficacy and waning rates were based on published clinical trial data. In the base-case analysis, vaccine coverage was assumed to be 40% with a second dose compliance of 95%. Costs and outcomes were discounted at 2% annually and the incremental cost-effectiveness ratio (ICER) was calculated from both a payer's and the societal perspective. Sensitivity analyses were carried out to explore the overall uncertainty in the model. RESULTS: Vaccination with RZV was projected to prevent 48,943 HZ cases and 12,136 PHN cases per million people aged ≥ 65 years compared with no vaccination. The incremental costs and quality-adjusted life years (QALYs) gained were ¥9.99 billion and 2314 QALYs from a payer's perspective and ¥9.34 billion and 2314 QALYs from a societal perspective. The resulting ICERs were approximately ¥4,320,000 and ¥4,040,000 per QALY gained from a payer's and the societal perspective, respectively. The ICER remained below a willingness-to-pay threshold of ¥5,000,000 for most sensitivity analyses carried out. CONCLUSION: Vaccination against HZ with RZV would be cost-effective compared with no vaccination for the Japanese population aged ≥ 65 years. TRIAL REGISTRATION: GSK study identifier: HO-16-17837. FUNDING: GlaxoSmithKline Biologicals SA.

The prevalence and disease burden of severe eosinophilic asthma in Japan.

Background: There are limited data on the prevalence and burden of severe eosinophilic asthma (SEA) both in Japan and globally. This study aimed to assess the prevalence and burden of SEA in Japan. Methods: This study was a retrospective, observational cohort analysis using health records or health insurance claims from patients with severe asthma treated at Kyoto University Hospital. The primary outcome was the prevalence of SEA, defined as a baseline blood eosinophil count ≥300 cells/µL. Secondary outcomes included frequency and risk factors of asthma exacerbations, and asthma-related healthcare resource utilization and costs. Results: Overall, 217 patients with severe asthma were included; 160 (74%) had eosinophil assessments. Of these, 97cases (61%), 54cases (34%), and 33cases (21%) had a blood eosinophil count ≥150, ≥300, and ≥500 cells/µL, respectively. Proportion of SEA was 34%. Blood eosinophil count was not associated with a significantly increased frequency of exacerbations. In the eosinophilic group, lower % forced expiratory volume in 1 second and higher fractional exhaled nitric oxide were predictive risk factors, while the existence of exacerbation history was a predictive risk factor for asthma exacerbations in the non-eosinophilic group. Severe asthma management cost was estimated as ¥357,958/patient-year, and asthma exacerbations as ¥26,124/patient-year. Conclusions: Approximately, one-third of patients with severe asthma in Japan have SEA. While risk factors for exacerbations differed between SEA and severe non-eosinophilic asthma, both subgroups were associated with substantial disease and economic burden. From subgroup analysis, blood eosinophil counts could be an important consideration in severe asthma management.

Burden of Herpes Zoster in the Japanese Population with Immunocompromised/Chronic Disease Conditions: Results from a Cohort Study Claims Database from 2005-2014.

INTRODUCTION: The aim of this study is to describe the disease burden and costs of herpes zoster (HZ) in the general adult Japanese population or patients with immunocompromised (IC) conditions or chronic disorders. METHODS: A retrospective cohort study of individuals aged 18-74 years was conducted using January 2005 to December 2014 records from the Japan Medical Data Center claims database. Twenty-eight IC conditions and chronic disorders were defined by diagnosis codes and/or procedures/treatments. HZ and its related complications were identified. Incidence rates (IR), frequency of HZ-related complications, healthcare resource utilization (HRU), and direct medical costs were estimated. HRU and costs were estimated on a subcohort of HZ cases occurring April 2012-January 2014. RESULTS: The overall IR of HZ in the total cohort of 2,778,476 adults was 4.92/1000 person-years (PY) [95% confidence interval (CI): 4.86-4.98] and increased with age. The IR in the IC cohort (51,818 subjects) was 8.87/1000 PY (95% CI: 8.29-9.48), ranging from 5.55/1000 PY (95% CI: 4.26-7.09) in psoriasis to 151.68/1000 PY (95% CI: 111.45-201.71) in hematopoietic stem cell transplant recipients; most IRs were in the range 6-10/1000 PY. The IRs in individuals with chronic disorders were also relatively high, in the range 5.40-12.90/1000 PY. The frequency of postherpetic neuralgia was 4.01% (95% CI: 3.72-4.33) in the total cohort and 11.73% (95% CI: 9.01-14.93) in the IC cohort. The mean [standard deviation (SD)] number of outpatient visits was 3.4 (4.9) and 5.0 (5.7), respectively, and the proportion of HZ patients hospitalized was 2.20% and 6.70%, respectively. The mean (SD) direct medical cost per HZ episode was ¥34,664 (¥54,433) and ¥55,201 (¥92,642) in the total and IC cohort, respectively. CONCLUSIONS: The elevated burden of HZ in Japanese individuals harboring IC conditions and chronic disorders documented in our study underlines the need for prevention of HZ in people with these conditions. FUNDING: GlaxoSmithKline Biologicals SA.

Disease severity and economic burden in Japanese patients with systemic lupus erythematosus: A retrospective, observational study.

AIM: To describe the healthcare resource utilization (HRU), direct medical costs and clinical characteristics for Japanese patients with mild, moderate or severe systemic lupus erythematosus (SLE). The primary objectives were to describe HRU and examine the direct medical costs for Japanese patients with mild, moderate, or severe SLE over the 3-year study period. Secondary objectives included recording patient demographics, clinical characteristics and frequency and cost of mild, moderate or severe flares. Exploratory objectives included a description of treatment patterns, and to explore which factors affect medical costs. METHODS: This retrospective, observational cohort study identified patients with SLE (diagnosed April 2010 to March 2012), from the Japan Medical Data Center claims database. RESULT: The study cohort comprised 295 patients with mild (28, 9.5%), moderate (134, 45.4%), or severe (133, 45.1%) SLE. Outpatient visits, hospitalizations and emergency room stays were experienced by 295 (100%), 116 (39.3%) and 31 (10.5%) patients, respectively, over the 3-year study period. Over the 3-year period, the mean total direct medical cost was US$27 004, and cost increased with SLE severity: mild, $5549 moderate, $15 290; and severe, $43 322 (analysis of variance, P < 0.0001). During this period, the majority of patients (282, 95.6%) experienced at least one flare episode and the mean (standard deviation) frequency was 5.5 (3.3) flares. The mean total direct medical cost per flare increased with SLE severity. CONCLUSION: This descriptive study provides information on the economic burden and clinical characteristics of Japanese patients with SLE based on claims data; high levels of HRU and direct medical costs were exhibited, particularly in patients with moderate or severe disease.

The Potential Public Health Impact of Herpes Zoster Vaccination of People Aged ≥ 50 Years in Japan: Results of a Markov Model Analysis.

INTRODUCTION: The aim of this study was to compare the public health impact of introducing two herpes zoster (HZ) vaccines into the vaccination programs for the Japanese population aged ≥ 50 years: a single-dose Varicella Vaccine Live (VVL) or a two-dose adjuvanted Recombinant Zoster Vaccine (RZV). METHODS: A multi-cohort static Markov model was developed to follow age cohorts (50-59, 60-69, 70-79 and ≥ 80 years) over their remaining lifetime. Japan-specific data inputs for the model were obtained from Japanese data sources. Age-stratified vaccine efficacy and waning rates were based on published clinical trial data. In the base-case analysis, vaccine coverage was assumed to be 40% for both vaccines, and compliance with second-dose of the RZV vaccine was set to 95%. RESULTS: Vaccination with RZV was projected to prevent approximately 3.3 million HZ cases, 692,000 cases of postherpetic neuralgia (PHN), and 281,000 cases of other complications, compared with the prevention of 0.8 million HZ cases, 216,000 PHN cases, and 57,000 other complications with vaccination with VVL. The number of individuals needed to vaccinate in order to prevent one HZ case ranged from 6 to 14 using RZV (depending on age and assumed second-dose compliance) and from 21 to 138 depending on age using VVL. By preventing a higher number of HZ cases and its complications, RZV vaccination led to fewer outpatient visits and hospitalizations than vaccination with VVL. CONCLUSION: Both vaccines had a positive public health impact compared to no vaccination, but due to its higher vaccine efficacy, RZV demonstrated a superior public health impact compared with VVL. FUNDING: GlaxoSmithKline Biologicals SA.

Resource Use and Cost of Treating Human Papillomavirus-Related Lesions in Japanese Women.

BACKGROUND: Human papillomavirus (HPV) infection is established as a necessary causal factor in several pathologies including cervical cancer (CC), which recorded over 11,000 new cases in 2011 in Japan. Nevertheless, cost burden data of human papillomavirus-related diseases in Japan are lacking. OBJECTIVES: To evaluate resource use and costs in women with HPV-related lesions. METHODS: A retrospective study using insurance claims databases was performed to assess the annual medical cost for suspected cervical intra-epithelial neoplasia (CIN)/CC, genital warts (GWs), CIN (all grades), and CC. Information on the treatment of GWs was obtained from the Claims Database developed by Japan Medical Data Center Co., Ltd. Information on CIN and CC was obtained from the Evidence-Based Medicine provider database developed by Medical Data Vision Co., Ltd. Databases cover about 1% of the Japanese population. Total annual cost in Japanese yen (¥) per patient in 2011 was calculated on the basis of resource used and unit costs from Japan medical insurance tariffs. RESULTS: Average annual costs were as follows: GWs, ¥34,424; suspected CIN/CC, ¥6,240; CIN 1, ¥17,484; CIN 2, ¥46,583; CIN 3, ¥166,227; and CC, ¥474,756. CONCLUSIONS: To our knowledge, this is the first observational study to estimate the annual medical costs of HPV-related diseases in Japan using real-world data collected in routine clinical practice. It could provide help in estimating the economic burden of HPV-related lesions in Japanese women.

Impact of Herpes Zoster and Post-Herpetic Neuralgia on Health-Related Quality of Life in Japanese Adults Aged 60 Years or Older: Results from a Prospective, Observational Cohort Study.

BACKGROUND AND OBJECTIVES: Herpes zoster (HZ) and its most frequent complication, post-herpetic neuralgia (PHN), have been shown to considerably impact quality of life (QoL). This has not yet been demonstrated in Japan. METHODS: QoL in HZ and PHN patients was evaluated using the Zoster Brief Pain Inventory (ZBPI), EuroQoL-5 Dimension (EQ-5D), Short-Form 12 version 2.0, and short-form McGill Pain Questionnaire up to 270 days after rash onset as part of a prospective, observational, cohort study conducted in Kushiro, Hokkaido, Japan. RESULTS: This study involved 412 adults ≥ 60 years of age diagnosed with HZ, 38 of whom developed PHN. QoL in daily activity performance and emotional and physical functioning was impaired at Day 0 (rash onset) and almost resolved by Day 90. Although the mean ZBPI worst pain score for HZ patients without PHN improved from 4.1 at Day 0 to 0.1 at Day 90, the score for HZ patients with PHN at Day 90 was comparable to that for HZ patients without PHN at Day 0. While the EQ-5D score in HZ without PHN improved, on average, from 0.755 to 0.949, the score for HZ with PHN was dependent on PHN duration and did not improve until PHN disappearance. CONCLUSIONS: HZ impaired QoL in daily activity performance and emotional and physical functioning. The negative impact on QoL was more prevalent in patients with a longer PHN duration compared with HZ without PHN. ClinicalTrials.gov identifier: NCT01873365.

Economic Burden of Herpes Zoster and Post-Herpetic Neuralgia in Adults 60 Years of Age or Older: Results from a Prospective, Physician Practice-Based Cohort Study in Kushiro, Japan.

BACKGROUND AND OBJECTIVE: Herpes zoster has a high incidence rate among people aged ≥ 60 years and can lead to serious complications such as post-herpetic neuralgia. There are currently no data on the economic burden of herpes zoster and post-herpetic neuralgia in Japan, and the objective of this study was to address this gap. METHODS: A total of 412 patients aged ≥ 60 years diagnosed with herpes zoster were recruited. Demographic, clinical, and healthcare resource utilization data on patients with herpes zoster or post-herpetic neuralgia collected via case report forms were used to estimate direct medical cost. Data obtained from a questionnaire survey among patients with herpes zoster/post-herpetic neuralgia were used to estimate transportation cost and productivity loss. RESULTS: The mean number of outpatient visits was 5.7. Prescription medications were the main cost driver accounting for 60% of the direct medical cost. The mean direct medical and total herpes zoster-related costs per patient were ¥43,925 and ¥57,112, respectively, and were higher in patients with post-herpetic neuralgia than in those with herpes zoster without complications. Direct medical cost represented 77%, productivity loss 19%, and transportation cost 4% of the total. CONCLUSIONS: This is the first study of the economic burden of herpes zoster and post-herpetic neuralgia in Japan and it demonstrated substantial direct medical cost as a result of the multiple outpatient visits and prescription medications required. These findings provide baseline data for possible future economic evaluations of new herpes zoster/post-herpetic neuralgia interventions. TRIAL REGISTRATION: This cost analysis is part of a prospective, physician practice-based cohort study conducted between June 2013 and February 2015 in Kushiro, Japan (Clinicaltrials.gov identifier NCT01873365, registered on 6 June, 2013).

Cost-Effectiveness Evaluation of the 10-Valent Pneumococcal Non-typeable Haemophilus influenzae Protein D Conjugate Vaccine and 13-Valent Pneumococcal Vaccine in Japanese Children.

INTRODUCTION: Diseases caused by Streptococcus pneumoniae represent a major public health problem. The purpose of this study was to compare, in the Japanese context, the projected health benefits, costs and cost-effectiveness of the latest generation of pneumococcal conjugate vaccines which may provide important insight into the potential public health impact of interventions in the context of local disease-specific epidemiology. METHODS: A Markov model was used to compare two vaccination strategies which involve routine infant immunization with either the 13-valent pneumococcal conjugate vaccine (PCV-13; Prevenar 13™, Pfizer, Pearl River, NY, USA) or the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV; Synflorix™, GlaxoSmithKline Biologicals SA, Rixensart, Belgium) over a time horizon of 5 years from the healthcare provider and societal perspectives. Estimates for key model parameters were obtained from locally available databases and published literature. Incremental benefits in terms of costs and quality-adjusted life-year and cost-effectiveness were assessed. RESULTS: A 3 + 1 vaccination schedule for infants with PHiD-CV is expected to have a similar impact on invasive pneumococcal disease and pneumonia and a larger impact on acute otitis media-related outcomes compared with PCV-13. Assuming price parity for these vaccines, the model projected that vaccination with PHiD-CV would result in cost savings of 1.9 and 3.9 billion Japanese yen from the provider and societal perspectives, respectively. This was largely due to a reduction in highly prevalent acute otitis media. Vaccination with PHiD-CV was expected to generate a gain of 433 quality-adjusted life-years compared to PCV-13 translating into dominance over PCV-13. Sensitivity analyses showed robustness of model outcome to changes in key model parameters and substantiated that the model outcome was consistently driven by the incremental benefit of PHiD-CV in averting acute otitis media. CONCLUSION: In comparison to PCV-13, vaccination with PHiD-CV is projected to be cost saving for Japan from both the healthcare provider and societal perspectives.

Effect of CYP2D6*10 on pharmacokinetic variability of routinely administered metoprolol in middle-aged and elderly Japanese patients.

OBJECTIVE: This study was performed to evaluate the effect of mutant alleles CYP2D6*2 and CYP2D6*10 on the pharmacokinetics of routinely administered metoprolol in middle-aged and elderly Japanese patients. METHODS: We determined the genotypes of CYP2D6 in 34 patients aged from 56 years to 83 years, and analyzed the plasma concentration of metoprolol at steady state after repetitive administration. The pharmacokinetic parameters of metoprolol in individual patients were obtained from population estimates according to Bayes' theorem. RESULTS: The plasma concentrations of metoprolol in the patients with CYP2D6*1/*1 (group 1a) were similar to those in the patients with CYP2D6*1/*2 (group 1b). The plasma concentrations in the patients with CYP2D6*1/*10 (group 2a) were also similar to those in the patients with CYP2D6*2/*10 (group 2b) but were higher than those in group 1 (group 1a plus 1b). The plasma concentrations of metoprolol in the patients with CYP2D6*10/*10 (group 3) were significantly higher than those in group 1 and group 2 (group 2a plus 2b). Mean values of oral clearance (in l/h/kg) in Groups 1, 2, and 3 were estimated to be 1.2, 1.0, and 0.49, respectively. These oral clearance values of metoprolol estimated in middle-aged and elderly Japanese patients were lower than those estimated in healthy young Chinese reported previously. CONCLUSION: The present study indicated that CYP2D6*10 is mainly responsible for the large pharmacokinetic variability of routinely administered metoprolol in middle-aged and elderly Japanese patients. In addition, the pharmacokinetics of repetitively administered metoprolol in middle-aged and elderly patients may be different from that of a single dose in younger patients. These results suggested that a lower dose of metoprolol may be used in middle-aged and elderly patients with CYP2D6*10.

The increased intestinal absorption rate is responsible for the reduced hepatic first-pass extraction of propranolol in rats with cisplatin-induced renal dysfunction.

The mechanisms responsible for the increased bioavailability of propranolol in renal dysfunction were investigated in rats. Experimental acute renal failure (ARF) was induced by intraperitoneal injection of cisplatin (5 mg kg(-1)). ARF induced a significant increase in blood propranolol concentration after intra-intestinal administration. The extent of bioavailability (F) of propranolol at an intestinal dose of 15 mg kg(-1) was 16.4% and 26.9% in control and ARF rats, respectively, and the F value at a 37.5 mg kg(-1) dose was 54.7% and 81.4% in control and ARF rats, respectively. In contrast, the blood propranolol concentration following intraportal infusion was not increased significantly in ARF rats. The hepatic first-pass extraction (E(h)) was dose-dependent and saturable: E(h) of propranolol in control rats was 58.0% and 18.3% at 8 and 20 mg kg(-1), respectively, and E(h) in ARF rats was 50.8% and 19.9% at 8 and 20 mg kg(-1), respectively. The initial absorption rate of propranolol from the intestine in ARF rats was significantly greater compared with control rats. These results indicated that the increased bioavailability of propranolol in rats with cisplatin-induced renal dysfunction was mainly a result of the increased absorption rate in the intestine followed by the partial saturation of hepatic first-pass metabolism.