Masahide Fukudo

Cerebrospinal Fluid Concentration of Erlotinib and its Active Metabolite OSI-420 in Patients with Central Nervous System Metastases of Non-small Cell Lung Cancer

Background: Although there have been several reports in which central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC) were improved by erlotinib, cerebrospinal fluid (CSF) penetration of erlotinib in such patients has not been reported. We investigated CSF concentrations of erlotinib and its active metabolite OSI-420. Method: We administered 150 mg erlotinib daily to four patients with NSCLC who had CNS metastases, and we investigated plasma pharmacokinetics of erlotinib and OSI-420 on days 1 and 8. In addition, we measured the concentrations of erlotinib and OSI-420 in CSF just before administration of erlotinib on day 8. Results: In all cases except for one case, plasma pharmacokinetics data on day 8 were similar to those previously reported. The mean ± SD CSF concentrations of erlotinib and OSI-420 were 54 ± 30 ng/ml and 10.8 ± 8.2 ng/ml, respectively. The mean ± SD CSF penetration rates of erlotinib and OSI-420 were 5.1% ± 1.9% and 5.8% ± 3.6%, respectively. CSF concentrations of erlotinib exceeded median inhibitory concentration (IC50) of erlotinib in intact tumor cells with wild-type epidermal growth factor receptor gene. Conclusion: The CSF penetrations of erlotinib and OSI-420 in patients with NSCLC who had CNS metastases were approximately 5.1% and 5.8%, respectively. This indicates that erlotinib can become a treatment option for CNS metastases of NSCLC.

Impact of MDR1 and CYP3A5 on the oral clearance of tacrolimus and tacrolimus-related renal dysfunction in adult living-donor liver transplant patients.

Objective The potential influence of the multidrug resistance 1 (MDR1) gene and the cytochrome P450 (CYP) genes, CYP3A4 and CYP3A5, on the oral clearance (CL/F) of tacrolimus in adult living-donor liver transplant patients was examined. Furthermore, the development of renal dysfunction was analyzed in relation to the CYP3A5 genotype. Methods Sixty de novo adult liver transplant patients receiving tacrolimus were enrolled in this study. The effects of various covariates (including intestinal and hepatic mRNA levels of MDR1 and CYP3A4, measured in each tissue taken at the time of transplantation, and the CYP3A5*3 polymorphism) on CL/F during the first 50 days after surgery were investigated with the nonlinear mixed-effects modeling program. Results CL/F increased linearly until postoperative day 14, and thereafter reached a steady state. The initial CL/F immediately after liver transplantation was significantly affected by the intestinal MDR1 mRNA level (P<0.005). Furthermore, patients carrying the CYP3A5*1 allele in the native intestine, but not in the graft liver, showed a 1.47 times higher (95% confidence interval, 1.17–1.77 times, P<0.005) recovery of CL/F with time than patients having the intestinal CYP3A5*3/*3 genotype. The cumulative incidence of renal dysfunction within 1 year after transplantation, evaluated by the Kaplan–Meier method, was significantly associated with the recipients but not donors CYP3A5 genotype (*1/*1 and *1/*3 vs. *3/*3: recipient, 17 vs. 46%, P<0.05; donor, 35 vs. 38%, P=0.81). Conclusion These findings suggest that the CYP3A5*1 genotype as well as the MDR1 mRNA level in enterocytes contributes to interindividual variation in the CL/F of tacrolimus in adult recipients early after living-donor liver transplantation. Furthermore, CYP3A5 in the kidney may play a protective role in the development of tacrolimus-related nephrotoxicity.

Population pharmacokinetic and pharmacogenomic analysis of tacrolimus in pediatric living‐donor liver transplant recipients

Our objective was to investigate the population pharmacokinetics of tacrolimus in pediatric living‐donor liver transplant recipients and examine the effects of the multidrug resistance 1 (MDR1) gene and the cytochrome P450 (CYP) genes CYP3A4 and CYP3A5 on the oral clearance of tacrolimus.

Pharmacodynamic analysis of tacrolimus and cyclosporine in living-donor liver transplant patients

The calcineurin inhibitors tacrolimus and cyclosporine (INN, ciclosporin) have been widely used to prevent allograft rejection after transplantation. We investigated pharmacodynamic properties of the 2 drugs and their clinical relevance in liver transplantation.

ABCG2 421C>A polymorphism and high exposure of sunitinib in a patient with renal cell carcinoma

Sunitinib is an oral multitargeted tyrosine kinase inhibitor (TKI) for renal cell carcinoma (RCC) [1]. Due to severe adverse effects, patients are forced to reduce or discontinue sunitinib, and discontinuation often leads to tumor regrowth. Breast cancer resistance protein (ABCG2) expressed in the intestine functions as an efflux pump of drugs. Among single-nucleotide polymorphisms (SNPs) in the ABCG2 gene, ABCG2 421C>A is the most common mutant allele in Asians ( 30%) [2]. This SNP was reported to be associated with an increase in oral bioavailability of several drugs including TKIs [2]. In the clinical setting, we experienced one RCC patient with severe adverse events early after oral administration. We then carried out pharmacokinetic and pharmacogenetic analyses of sunitinib, focusing on ABCG2. Five RCC patients, three men and two women [mean age: 55.6 (34–67)], were analyzed. All five patients started 50 mg of sunitinib once a day. Adverse events were graded by National Cancer Institute—Common Toxicity Criteria for Adverse Effects v3.0. This study was approved by Kyoto University Graduate School and Faculty of Medicine Ethics Committee. Blood samples were collected on day 8, and plasma concentrations of sunitinib and its major metabolite SU012662 were determined by high-performance liquid chromatography (HPLC). HPLC conditions were as follows: column, GEMINI-NX 3 lm C18 (4.6 · 150 mm); mobile phase, acetate buffer in methanol at 33 : 67 (sunitinib) and 40 : 60 (SU012662) and wavelength, 423 nm. The SNP was determined by direct sequencing. Cell culture, transfection and transport experiments were carried out as described previously with a slight modification [3, 4]. One patient (patient 1) showed severe adverse events such as hypertension (grade 3), facial acne (grade 3) and elevation of amylase (grade 3). The maximum concentration and area under the concentration–time curve of sunitinib in patient 1 were 2.5-fold higher than in the other four patients (Figure 1A). Plasma concentration profiles of SU012662, a major metabolite of sunitinib, were comparable among patients (data not

Distinct Inhibitory Effects of Tacrolimus and Cyclosporin A on Calcineurin Phosphatase Activity

We have compared the pharmacodynamic properties of calcineurin inhibitors tacrolimus and cyclosporin A in rats to clarify the different therapeutic drug monitoring strategy of both drugs in a clinical situation. In various tissue extracts, the inhibition of calcineurin activity by cyclosporin A was significantly greater than that by tacrolimus at the same drug concentration (1 μM) in the thymus, heart, liver, spleen, kidney, and testis (p < 0.05). The time profiles of blood concentrations and calcineurin activity in whole blood were examined after single or repeated administration of each drug in rats. A substantial time delay in the inhibition was observed following the single administration of tacrolimus or cyclosporin A, resulting in an anticlockwise hysteresis in the relationship between blood concentrations and calcineurin inhibition in whole blood. In contrast, such a hysteresis loop diminished after the repeated administration of each drug, and the recovery rate of calcineurin activity was greater for the inhibition induced by cyclosporin A than by tacrolimus. Furthermore, tacrolimus produced a comparable inhibition of calcineurin activity in whole blood at lower blood concentrations than cyclosporin A. Overall, the effect compartment model well described the time profiles of calcineurin activity in whole blood after the single and repeated administrations of each drug. These findings suggest that the properties of calcineurin inhibition differ between tacrolimus and cyclosporin A. Distinct pharmacodynamics may partly contribute to the therapeutic drug monitoring strategy in transplant patients receiving calcineurin inhibitors.

The effect of ABCG2 genotype on the population pharmacokinetics of sunitinib in patients with renal cell carcinoma.

Background: Sunitinib, a multitargeted tyrosine kinase inhibitor, offers favorable therapeutic outcomes to patients with advanced renal cell carcinoma. However, to maximize the clinical benefits, an effective therapeutic management strategy with dose optimization is essential. The objectives of this analysis were to describe the pharmacokinetics (PK) of sunitinib by a population PK approach and to quantitatively evaluate the effect of potential predictive factors including ABCG2 genotype on the PK of sunitinib. Methods: Plasma concentration–time profiles at 3 consecutive days including a total of 245 sunitinib plasma concentrations were available from 19 Japanese patients with renal cell carcinoma. Blood samples were collected on days 2, 8, and 15 after the start of the therapy. Population PK analysis was performed using NONMEM 7.2. Body weight, gender, and genotype of ABCG2 421C>A were evaluated as potential covariates. Interoccasion variability (IOV) among the 3 sampling days was also assessed as a random effect parameter. Results: The sunitinib PK profiles were best described by a 1-compartment model with first-order absorption. The ABCG2 421C>A genotype was identified as a significant covariate for the prediction of oral clearance (CL/F). No significant improvement in model fit was observed by including body weight and/or gender. A systematic difference in estimated population CL/F was observed between days 2 and 8, which was quantified as approximately 30% decrease over time. This difference was described as a covariate for CL/F in the model. IOV included as a random effect parameter significantly improved the model fit. Conclusions: This analysis provides a population PK model of sunitinib with the ABCG2 421C>A genotype as a predictive covariate for CL/F. It also suggests that IOV and change of CL/F over time need to be considered to predict the sunitinib PK more accurately. These findings will be implemented to optimize the pharmacotherapy of sunitinib.

A Case of Radiation Recall Pneumonitis Induced by Erlotinib, Which Can be Related to High Plasma Concentration

To the Editor: A 78-year-old currently smoking Japanese man was diagnosed with nonsmall cell lung cancer (NSCLC). The histology was adenocarcinoma, and the primary stage was cT2N3M0. Epidermal growth factor receptor (EGFR) gene mutations were not evaluated. After he received four courses of chemotherapy (carboplatin and paclitaxel) and sequential radiation (60 Gy), he achieved partial response. The volume of lung receiving 20 Gy (V20) was 33% (Figure 1A). Seven months after finishing radiation, his chest computed tomography (CT) revealed pulmonary metastases and pleural disseminations (Figure 1B). The treatment started with daily administration of 150 mg erlotinib. Fourteen days after starting administration of erlotinib, his chest CT revealed right lung consolidation localized within the previously irradiated area (Figure 1C), so we diagnosed him with radiation recall pneumonitis induced by erlotinib (grade 3, Radiation Therapy Oncology Group scoring criteria). Twenty-four hours after last administration of erlotinib, we investigated his plasma concentration of erlotinib by high-performance liquid chromatography with ultraviolet detection as previously reported.1 The plasma concentration of erlotinib was 3817 ng/ mL, which was very high compared with previously reported mean concentration (1642.00 ng/mL).2 After he stopped administration of erlotinib and received systemic corticosteroid therapy, his symptoms improved. When radiotherapy is followed by chemotherapy, subclinical damage from irradiation can be unmasked and clinically manifested. This is called radiation recall phenomenon. Radiation recall pneumonitis is a very rare reaction in a previously irradiated area of pulmonary tissue after application of a pharmacological agent. Erlotinib is an EGFR tyrosine kinase inhibitor (TKI) and has been studied in patients with NSCLC. From Food and Drug Administration (FDA) drug approval summary, the incidence of interstitial lung disease (ILD), which is sometimes fatal, associated with erlotinib is estimated at 0.8%.3 The reaction of radiation recall pneumonitis is similar to that of druginduced ILD in that both are associated with a specific drug. No case of radiation recall pneumonitis induced by erlotinib has been reported. In this article, we present a first case report of radiation recall pneumonitis induced by erlotinib and investigate the plasma concentration of erlotinib. Fatal radiation pneumonitis is not usually observed with a lung V20 of 33%. In contrast, a case of symptomatic pneumonitis (grade 3) from radiation (V20 of 31%) and concurrent erlotinib has been reported.4 Moreover, EGFRTKIs have been reported to act as potent radiation sensitizers.5 From these findings, erlotinib can tend to induce radiation recall pneumonitis, especially in Japanese patients. In this case, the plasma concentration of erlotinib was very high compared with previous reported data.2 Although radiation recall pneumonitis induced by erlotinib could be related to a high plasma concentration of erlotinib, there is no report about this relationship. The relationship between ILD associated with erlotinib and erlotinib plasma concentration is also unclear. If ILD is related to erlotinib plasma concentration, the plasma concentration should be investigated when erlotinib is administered to a patient with the risk factors for ILD and the dose can be decreased.

Pharmacokinetics of erlotinib and its active metabolite OSI-420 in patients with non-small cell lung cancer and chronic renal failure who are undergoing hemodialysis.

Introduction: Although erlotinib, an orally active and selective tyrosine kinase inhibitor of epidermal growth factor receptor, is mainly metabolized in the liver, its effectiveness and safety for patients with chronic renal failure (CRF) undergoing hemodialysis (HD) has not been reported. Thus, we investigated the pharmacokinetics (PK) of erlotinib and its active metabolite OSI-420 in such patients with nonsmall cell lung cancer (NSCLC). Method: We administered 150 mg erlotinib daily to three patients with NSCLC and CRF undergoing HD (HD group) and five patients with NSCLC and normal organ function (control group) and analyzed the PK of erlotinib and OSI-420. In the HD group, PK analyses were performed on day 1 (off HD), day 8 (off HD), and day 9 (on HD) after starting administration of erlotinib, and in the control group, they were performed on day 1 and day 8. Results: In the HD group, there were little differences in the PK data between day 8 and day 9. The PK data on day 1 and day 8 of the HD group were also similar to those of the control group. There were no serious adverse events in any cases, and one of the HD patients achieved partial response. Conclusion: Erlotinib was hardly affected by renal function and HD, which confirms the effectiveness and safety of erlotinib treatment in patients with NSCLC and CRF undergoing HD. Erlotinib can become one treatment option for such patients.

Forecasting of Blood Tacrolimus Concentrations Based on the Bayesian Method in Adult Patients Receiving Living-Donor Liver Transplantation

Objective: To evaluate Bayesian prediction of blood tacrolimus concentrations in adult patients receiving living-donor liver transplantation (LDLT) using previously obtained population pharmacokinetic parameters.Patients and methods: Data were retrospectively collected from 47 adult patients receiving LDLT who were not included in the estimation of population pharmacokinetic parameters. Blood tacrolimus concentrations were predicted without or with the empirical Bayesian method using sparse samples obtained in the previous week. Predictive performance of the concentrations was evaluated by the mean prediction error (ME), mean absolute prediction error (MAE) and root mean square error (RMSE) as well as the percentage of successful predictions (percentage of absolute prediction error less than 3 μg/L, %PRED3).Results: Concentrations predicted by the population mean pharmacokinetic parameter values coincided well with observed concentrations during the period of tacrolimus infusion immediately after the operation. For concentrations during subsequent oral therapy with tacrolimus, predictability by the population mean pharmacokinetic parameter values alone was not satisfactory. Bayesian forecasting using one or two blood concentrations obtained in the previous week significantly decreased (p < 0.05) MAE and RMSE compared with predictions based on the population mean pharmacokinetic parameters on postoperative days 21 and 28, but not on day 14. During postoperative days 15–21, %PRED3 was increased to 68.6% or 71.2% with the Bayesian method using one or two blood concentrations, respectively, from 44.9% with the population mean pharmacokinetic parameter values.Conclusion: The present study demonstrated the applicability of the Bayesian method with use of one or two samples for prediction of blood tacrolimus concentrations in adult patients receiving LDLT.OBJECTIVE To evaluate Bayesian prediction of blood tacrolimus concentrations in adult patients receiving living-donor liver transplantation (LDLT) using previously obtained population pharmacokinetic parameters. PATIENTS AND METHODS Data were retrospectively collected from 47 adult patients receiving LDLT who were not included in the estimation of population pharmacokinetic parameters. Blood tacrolimus concentrations were predicted without or with the empirical Bayesian method using sparse samples obtained in the previous week. Predictive performance of the concentrations was evaluated by the mean prediction error (ME), mean absolute prediction error (MAE) and root mean square error (RMSE) as well as the percentage of successful predictions (percentage of absolute prediction error less than 3 microg/L, %PRED3). RESULTS Concentrations predicted by the population mean pharmacokinetic parameter values coincided well with observed concentrations during the period of tacrolimus infusion immediately after the operation. For concentrations during subsequent oral therapy with tacrolimus, predictability by the population mean pharmacokinetic parameter values alone was not satisfactory. Bayesian forecasting using one or two blood concentrations obtained in the previous week significantly decreased (p<0.05) MAE and RMSE compared with predictions based on the population mean pharmacokinetic parameters on postoperative days 21 and 28, but not on day 14. During postoperative days 15-21, %PRED3 was increased to 68.6% or 71.2% with the Bayesian method using one or two blood concentrations, respectively, from 44.9% with the population mean pharmacokinetic parameter values. CONCLUSION The present study demonstrated the applicability of the Bayesian method with use of one or two samples for prediction of blood tacrolimus concentrations in adult patients receiving LDLT.