Limited sampling strategies for the estimation of atazanavir daily exposure in HIV‐infected patients

Stepwise multiple regression analyses were applied to 44 atazanavir pharmacokinetic profiles from 44 HIV‐1 infected patients concomitantly treated with raltegravir with the goal of identifying limited sampling strategies for the prediction of drug AUC_0–12. Atazanavir trough‐based equations failed to reliably predict daily drug exposure in patients with low drug bioavailability. Conversely, different algorithms based on few samples and associated with good correlation, acceptable bias and imprecision with the measured atazanavir AUC_0–12 were identified. These models could be used to predict atazanavir exposure for clinic or research purposes.     

Population pharmacokinetics of tacrolimus in adult kidney transplant recipients

OBJECTIVES: The aims of this study were to investigate the population pharmacokinetics of tacrolimus in adult kidney transplant recipients and to identify factors that explain variability. METHODS: Population analysis was performed on retrospective data from 70 patients who received oral tacrolimus twice daily. Morning blood trough concentrations were measured by liquid chromatography-tandem mass spectrometry. Maximum likelihood estimates were sought for apparent clearance (CL/F) and apparent volume of distribution (V/F), with the use of NONMEM (GloboMax LLC, Hanover, Md). Factors screened for influence on these parameters were weight, age, gender, postoperative day, days of tacrolimus therapy, liver function tests, creatinine clearance, hematocrit fraction, corticosteroid dose, and potential interacting drugs. RESULTS: CL/F was greater in patients with abnormally low hematocrit fraction (data from 21 patients only), and it decreased with increasing days of therapy and AST concentrations (P <.01). Average parameter estimates were as follows: CL/F = 31.8 L/h (hematocrit <0.33), CL/F = 24.2 L/h (hematocrit >0.33), and V/F = 2080 L. Marked interindividual variability (42% to 111%) and residual random error (3.7 ng/mL) were observed. On the basis of the derived model, a patient with normal AST (20 U/L) or high AST (200 U/L) concentrations 7 days after commencement of therapy would require a tacrolimus dose of 4.6 mg or 4.0 mg, respectively, to achieve a steady-state trough concentration of 10 ng/mL. CONCLUSIONS: The population pharmacokinetics of tacrolimus in adult kidney transplant recipients showed wide variability. Thus it is not possible to use a standard tacrolimus dose as an empiric predictor of concentration in this population. An understanding of factors that influence the pharmacokinetics of tacrolimus may assist in drug dosage decisions.     

A randomized crossover study comparing different tacrolimus formulations to reduce intrapatient variability in tacrolimus exposure in kidney transplant recipients

A high intrapatient variability (IPV) in tacrolimus exposure is a risk factor for poor long‐term outcomes after kidney transplantation. The main objective of this trial was to investigate whether tacrolimus IPV decreases after switching patients from immediate‐release (IR)‐tacrolimus to either extended‐release (ER)‐tacrolimus or LifeCyclePharma (LCP)‐tacrolimus. In this randomized, prospective, open‐label, cross‐over trial, adult kidney transplant recipients on a stable immunosuppressive regimen, including IR‐tacrolimus, were randomized for conversion to ER‐tacrolimus or LCP‐tacrolimus, and for the order in which IR‐tacrolimus and the once‐daily formulations were taken. Patients were followed 6 months for each formulation, with monthly tacrolimus predose concentration assessments to calculate the IPV. The IPV was defined as the coefficient of variation (%) of dose corrected predose concentrations. Ninety‐two patients were included for analysis of the primary outcome. No significant differences between the IPV of IR‐tacrolimus (16.6%) and the combined once‐daily formulations (18.3%) were observed (% difference +1.7%, 95% confidence interval [CI] −1.1% to ‒4.5%, p = 0.24). The IPV of LCP‐tacrolimus (20.1%) was not significantly different from the IPV of ER‐tacrolimus (16.5%, % difference +3.6%, 95% CI −0.1% to 7.3%, p = 0.06). In conclusion, the IPV did not decrease after switching from IR‐tacrolimus to either ER‐tacrolimus or LCP‐tacrolimus. These results provide no arguments to switch kidney transplant recipients from twice‐daily (IR) tacrolimus formulations to once‐daily (modified‐release) tacrolimus formulations when the aim is to lower the IPV.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

High intrapatient variability (IPV) in tacrolimus exposure is associated with poor kidney transplant outcomes. Different causes of a high IPV are considered, like drug‐drug interactions, food intake, and adherence and the type of tacrolimus formulation.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Does switching from a twice‐daily immediate‐release (IR) formulation to a once‐daily modified‐release tacrolimus formulation with a flatter pharmacokinetic (PK) profile lower the IPV of tacrolimus in stable kidney transplant recipients?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

We could not demonstrate a decrease in tacrolimus IPV after switching from IR‐ to modified‐release tacrolimus formulations in stable kidney transplant recipients. Tremor, an important side effect of tacrolimus, seems to occur less frequently with LifeCyclePharma‐tacrolimus compared to IR‐tacrolimus.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Tacrolimus IPV seems not to be influenced by different PK profiles of the different tacrolimus formulations.     

Limited sampling strategy for the estimation of mycophenolic acid area under the curve in adult renal transplant patients treated with concomitant tacrolimus

BACKGROUND: Significant relationships between the mycophenolic acid (MPA) area under the concentration-time curve (AUC(0-12h)) and the risks for acute rejection and side effects have been reported. We developed a practical method for estimation of MPA AUCs. Regression equations were developed using repeated cross-validation for randomly chosen subsets, characterized statistically, and verified for acceptable performance. METHODS: Twenty-one renal transplant patients receiving 0.5 or 1.0 g of mycophenolate mofetil twice daily and concomitant tacrolimus provided a total of 50 pharmacokinetic profiles. MPA concentrations were measured by a validated HPLC method in 12 plasma samples collected at predose and at 30 and 60 min; 2, 3, 4, 6, 8, 9, 10, 11, and 12 h; 1 and 2 weeks; and 3 months after transplantation. Twenty-six 1-, 2-, or 3-sample estimation models were fit (r(2) = 0.341-0.862) to a randomly selected subset of the profiles using linear regression and were used to estimate AUC(0-12h) for the profiles not included in the regression fit, comparing those estimates with the corresponding AUC(0-12h) values, calculated with the linear trapezoidal rule, including all 12 timed MPA concentrations. The 3-sample models were constrained to include no samples past 2 h. RESULTS: The model using c(0h), c(0.5h), and c(2h) was superior to all other models tested (r(2) = 0.862), minimizing prediction error for the AUC(0-12h) values not included in the fit (i.e., the cross-validation error). The regression equation for AUC estimation that gave the best performance for this model was: 7.75 + 6.49c(0h) + 0.76c(0.5h) + 2.43c(2h). When we applied this model to the full data set, 41 of the 50 (82%) estimated AUC values were within 15% of the value of AUC(0-12h) calculated using all 12 concentrations. CONCLUSIONS: This limited sampling strategy provides an effective approach for estimation of the full MPA AUC(0-12h) in renal transplant patients receiving concomitant tacrolimus therapy.     

Pharmacokinetics of apixaban and tacrolimus or cyclosporine in kidney and lung transplant recipients

Apixaban is frequently used off‐label in transplant recipients. However, a potential drug interaction exists with the calcineurin inhibitors. We conducted an open‐label drug–drug interaction study to determine the pharmacokinetics of apixaban in lung and kidney transplant recipients who were taking a calcineurin inhibitor. A single dose of apixaban 10 mg was administered orally to kidney and lung transplant recipients maintained on either tacrolimus or cyclosporine, and pharmacokinetic parameters were compared to a reference cohort of 12 healthy subjects who used the same apixaban dose and pharmacokinetic blood sampling. Fourteen participants were enrolled (n = 6 kidney, n = 8 lung), with 10 maintained on tacrolimus and four on cyclosporine. Data from 13 participants was usable. Participants were taking triple therapy immunosuppression and had a mean (SD) of 12 (3) medications. Participants receiving tacrolimus and cyclosporine had area under the plasma concentration–time curve from time zero to infinity (AUC_0‐inf) geometric least square means (90% confidence interval [CI]) of 4312 (95% CI 3682, 5049) and 5388 (95% CI 3277, 8858), respectively. Compared to healthy subjects, the associated geometric mean ratios (GMRs) for apixaban maximum plasma concentration (C_max), AUC from time zero to the last quantifiable concentration (AUC_0‐tlast) and AUC_0‐inf were 197% (95% CI 153, 295), 244% (95% CI 184, 323), and 224% (95% CI 170, 295) for transplant recipients on tacrolimus. The GMR (90% CI) C_max, AUC_0‐tlast, and AUC_0‐inf of apixaban for patients on cyclosporine were 256% (95% CI 184, 358), 287% (95% CI 198, 415), and 280% (95% CI 195, 401). Kidney and lung transplant recipients receiving tacrolimus had higher apixaban exposure. A similar trend was noted for patients receiving cyclosporine, but additional patients are needed to confirm this interaction. Future studies are needed before apixaban can be safely recommended in this population, and the impact of dose staggering should be investigated. This study highlights the importance of pharmacokinetic studies in actual patient populations.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Apixaban is frequently used off label in transplant recipients. However, a potential drug interaction exists with the calcineurin inhibitors. A randomized crossover drug–drug interaction study in healthy subjects suggested that the combination of apixaban and calcineurin inhibitors is safe, but this has not been evaluated in actual patients.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study explored the pharmacokinetics of apixaban in lung and kidney transplant recipients in a real‐world setting to determine the impact of calcineurin use on apixaban systemic exposure.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Kidney and lung transplant recipients receiving tacrolimus experienced significantly higher apixaban exposure compared with healthy subjects receiving apixaban alone, and there was a similar trend for patients receiving cyclosporine.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Significantly higher apixaban exposure suggests that future studies are needed before this drug can be safely recommended in this population, and highlight the importance of pharmacokinetic studies in actual patient populations.     

脑死亡供肾肾移植受者的近期状况分析

背景:供者短缺严重限制了肾移植的发展,脑死亡供肾在一定程度上缓解了供肾短缺的问题。目的:比较脑死亡供肾与尸体供肾肾移植患者移植后短期预后情况,初步探讨脑死亡供者在肾移植临床应用中的安全性。方法:回顾性分析肾移植90例患者移植过程中和移植后情况,其中80例供者为尸体供肾,10例为脑死亡供肾,比较两组受者移植中出血量、手术时间、移植后移植肾功能恢复情况、各种并发症的发生率及移植后近期生存情况(围手术期、移植后6个月)的差异。结果与结论:两组间移植时间、移植过程中出血量比较差异无显著性意义,移植后1,6个月生存率及移植后并发症的发生率比较,差异亦无显著性意义。说明脑死亡供肾与尸体供肾肾移植患者移植后早期预后无明显差异,安全可靠。     

Lipidomics of cyclophosphamide 4‐hydroxylation in patients receiving post‐transplant cyclophosphamide

Biomarker‐guided dosing may improve the efficacy and toxicity of cyclophosphamide (CY); however, clinical studies evaluating their association with the area under the plasma concentration–time curve (AUC) of CY and its metabolites are time‐ and resource‐intensive. Therefore, we sought to identify lipidomic biomarkers associated with the time‐varying differences in CY formation clearance to 4‐hydroxycyclophosphamide (4HCY), the principal precursor to CY''s cytotoxic metabolite. Hematopoietic cell transplant (HCT) patients receiving post‐transplant CY (PT‐CY) were enrolled, cohort 1 (n = 25) and cohort 2 (n = 26) donating longitudinal blood samples before they started HCT (pre‐HCT), before infusion of the donor allograft (pre‐graft), before the first dose of PT‐CY (pre‐CY) and 24 h after the first dose of PT‐CY (24‐h post‐CY) which is also immediately before the second dose of CY. A total of 409 and 387 lipids were quantitated in the two cohorts, respectively. Associations between lipids, individually and at a class level, and the ratio of 4HCY/CY AUC (i.e., 4HCY formation clearance) were evaluated using linear regression with a false discovery rate <0.05. There were no individual lipids that passed control for false discovery at any time point. These results demonstrate the feasibility of lipidomics, but future studies in larger samples with multiple omic tools are warranted to optimize CY dosing in HCT.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

The old yet commonly used drug cyclophosphamide (CY) has a complex pharmacokinetic disposition. There is a paucity of information regarding the formation clearance of 4‐hydroxycyclophosphamide (4HCY), the precursor to CY’s primary cytotoxic metabolite phosphoramide mustard. To date, scientists have not been able to create a more effective or safer analog to CY or to identify a precision medicine tool consistently associated with the efficacy, toxicity, or pharmacokinetics of CY.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study addresses the question if the plasma lipidome before post‐transplant cyclophosphamide (PT‐CY) administration in hematopoietic cell transplant (HCT) patients is associated with the ratio of 4HCY/CY area under the plasma concentration–time curve (AUC).

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study shows that longitudinal collection of plasma lipidomic samples is feasible in HCT patients receiving PT‐CY. However, in this small patient population, we could not find an association of the plasma lipidome with the ratio of 4HCY/CY AUC. Furthermore, this study shows that the plasma lipidome changes over the ~21‐day period that starts before HCT to 24‐h after the first PT‐CY dose. This study is also among the first to evaluate the plasma lipidome in HCT patients.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study shows how interrogating the plasma lipidome may provide insight into the pharmacokinetics of CY and how interrogating the plasma lipidome is feasible for biomarker studies.     

Effect of coadministered HIV-protease inhibitors on tacrolimus and sirolimus blood concentrations in a kidney transplant recipients

A patient with human immunodeficiency virus infection and end-stage renal disease received a renal transplant. At the time of surgery, the patient was on quadruple antiretroviral therapy (lamivudine, zidovudine, and amprenavir/ritonavir). Immunosuppression was initiated with basiliximab, corticosteroid, mycophenolate mofetil, and a single 0.5 mg dose of tacrolimus. In the following days, an increase in tacrolimus concentration was observed with a peak of 37 ng/mL. Tacrolimus half-life was 6.5 days and tacrolimus maintenance dose was 0.5 mg every 4 days. Eleven months later, the patient had developed Kaposi sarcoma. Tacrolimus was replaced by sirolimus (first dose 1 mg), and the patient was stabilized with 1.5 mg of sirolimus once a week. Increased tacrolimus half-life and increased dose interval of sirolimus and tacrolimus were due to CYP3A4/5 and/or P-glycoprotein inhibition by protease inhibitors. Close monitoring is required in the management of tacrolimus and sirolimus dosing regimens when combined with ritonavir boosted HIV-1 protease inhibitors.     

肾移植术后不同时间麦考酚酸暴露量的变化——附16例报告

目的:观察肾移植术后不同时间麦考酚酸暴露量的变化,为肾移植术后麦考酚吗乙酯剂量的调整提供理论依据.方法:16例首次肾移植患者,均于肾移植术后24小时内给予麦考酚吗乙酯(mycophenolate mofetil,MMF)1.5 g/d治疗,长期应用.于术后第7日、第28日、第90日测定其服药前、服药后半小时及服药后2小时的麦考酚酸的血药浓度,采用Shaw简易公式计算对应的麦考酚酸血药浓度-时间曲线下面积(the area under the drug concentration in the plasma versurs time curve,AUC)并比较其差异.结果:术后第7日、第28日、第90日的麦考酚酸AUC分别为(32±9)(mg/L)·h、(41±10)(mg/L)·h和(47±13)(mg/L)·h,比较差异均有统计学意义(均为P＜0.05).结论:在术后3个月内连续服用同等剂量(1.5 g/d)MMF的情况下,麦考酚酸AUC逐渐升高,在术后第90日达到(47±13)(mg/L)·h,已超过能有效预防急性排斥反应的AUC.提示应在用药的90日内监测麦考酚酸AUC,并及时减少用量,以免发生严重的不良反应.     

Two sampling time profiles for the abbreviated estimation of mycophenolic acid area under the curve in adult renal transplant recipients treated with mycophenolate mofetil and concomitant tacrolimus

Objective: Various studies have revealed that mycophenolic acid (MPA) area under the time‐concentration curve (AUC) may have clinical value in mycophenolate mofetil dose adjustment. As the full AUC measurement is impractical in clinical practice, several abbreviated AUC profiles using pre‐dose, and two or three post‐dose samples have been proposed; however, the possible use of lower sampling time profiles has an unquestionable practical interest, and the aim of our study was the evaluation of several two‐points algorithms using only one post‐dose sample. Patients and methods: In 60 MPA concentration‐time profiles from 37 adult renal transplant patients treated with mycophenolate mofetil and concomitant tacrolimus, the MPA AUC values were estimated using the three sampling time algorithm (pre‐dose, one‐half and 2 h post‐dose) of Pawinski et al. (Clinical Chemistry 48, 2002, 1497), trapezoidal extrapolated procedure according to Hale et al. (Clinical Pharmacology Therapeutics 64, 1998, 672), and two‐points algorithm (pre‐dose and 2 h post‐dose) proposed by David‐Neto et al. (Clinical Transplantation 19, 2005,19). Results: The AUC values estimated using the algorithm of Pawinski et al. had a very high correlation (r = 0·997, P < 0·001) with the trapezoidal extrapolated AUC results. The estimated AUC values obtained using the two‐points algorithm of David‐Neto et al. present a high correlation (r = 0·930, P < 0·001), acceptable mean prediction error (+3·3 ± 1·8%), and a diagnostic efficiency of 94% in the classification of subtherapeutic, therapeutic, and supratherapeutic values, with respect to the three‐points algorithm of Pawinski et al. Conclusion: The two sampling time algorithm of David‐Neto gave similar results to those of the three‐sampling time algorithm of Pawinski, and both, with sampling over 2 h, may be useful for routine MPA AUC estimation in renal transplant recipients with concomitant tacrolimus. Both are unsuitable when unusually unpredictable pharmacokinetics are expected such as with enteric‐coated formulations.     

CYP3A5 genotype markedly influences the pharmacokinetics of tacrolimus and sirolimus in kidney transplant recipients

It is currently not clear whether the concentration-time curves of the immunosuppressants differ with respect to the CYP3A5, MDR1, or MRP2 genotype in dose-adapted stable kidney transplant patients. Dose/trough concentration ratios were obtained in 134 tacrolimus and 20 sirolimus-treated patients, and plasma concentration-time profiles were obtained from 16 (tacrolimus) and 10 (sirolimus) patients. Genotyping was carried out for CYP3A5 6986A>G; ABCB1 2677G>T/A, 3435C>T and ABCC2 -24C>T; 1249G>A; 3972C>T. Dose/trough concentration ratios were 0.67+/-0.3 and 1.36+/-0.73 x 10(3) l (P<0.00001) for tacrolimus and 0.42+/-0.17 and 0.84+/-0.46 x 10(3) l (P=0.18) for sirolimus in CYP3A5 non-expressors and expressors. The unadjusted tacrolimus area under curve (AUC)(0-12) was 106.8+/-17.5 ng/ml x h compared with 133.3+/-42.2 ng/ml x h (P=0.37) without affecting serum creatinine. Mean unadjusted AUC(0-24) of sirolimus did not differ significantly either. Therefore, CYP3A5 expressor status and not transporter variants is a main determinant of oral clearance, particularly for tacrolimus. Dose adaptation according to trough levels, however, appears to be sufficient to maintain similar concentration-time profiles.     

A comparison of measured trough levels and abbreviated AUC estimation by limited sampling strategies for monitoring mycophenolic acid exposure in stable heart transplant patients receiving cyclosporin A-containing and cyclosporin A-free immunosuppressive regimens

BACKGROUND: Mycophenolate mofetil (NIMF) pharmacokinetics vary widely, and enterohepatic recirculation of the drug and its metabolites may be altered by concurrently administered immunosuppressants, including the widely used agent cyclosporin A (CsA). A reliable method of achieving effective and well-tolerated levels of NIMF-based immunosuppression would be of eminent interest. OBJECTIVE: This study compared the use of measured mycophenolic acid (MPA) trough levels (C0) and abbreviated AUC estimation by limited-sampling strategies for monitoring MPA exposure in stable heart transplant recipients (>1 year after transplantation) receiving a CsA-containing or CsA-free immunosuppressive regimen. METHODS: The treatment groups were receiving chronic maintenance immunosuppressive regimens consisting of either CsA/MMF or rapamycin (RAPA)/MMF. An additional subgroup of patients was switched from the CsA-containing regimen to the RAPA-containing regimen. Fasting venous blood samples were obtained before dosing and at 40, 75, 120, and 240 minutes after administration of the morning dose of MME The validated Emit assay was used to measure MPA plasma concentrations. Dose adjustment of AUCs was performed by dividing the AUC by the morning NIMF dose in grams. Cmax after administration of the morning dose was determined from available MPA data points using curve-fitting analysis. The increase to Cmax (Cmax-C0) was calculated, and dose adjustment was performed as before. Abbreviated 12-hour MPA AUCs were estimated using a limited-sampling strategy (before dosing and 30 and 120 minutes after dosing) based on high-performance liquid chromatography data. Adverse events were monitored during routine follow-up visits. RESULTS: The study included 47 patients receiving CsA/MMF, 15 receiving RAPA/MMF, and 9 who were switched from CsA/MMF to RAPA/MME The population included 55 men and 7 women, with a mean age of 58.94 years and a mean weight of 81.85 kg. The only significant differences in baseline clinical characteristics between groups were the mean number of years since heart transplantation (3.62 CsA/MMF vs 8.53 RAPA/MMF; P<0.01) and the proportions of patients still receiving corticosteroids (44.7% vs 13.3%, respectively; P<0.01). Reported adverse events were generally mild, including leukopenia (8.1%), diarrhea (6.5%), and abdominal pain (4.8%), and did not require drug discontinuation. In patients receiving CsA/MMF, MPA AUCs ranged from 19.67 to 81.80 mg/h.L (mean [SD], 41.92 [14.14] mg/h.L). MPA Co levels were poorly correlated with total AUC (r2=0.36). MPA Co levels of 0.5 and 1.6 mg/L were correlated with AUCs of <30 and <40 mg/h.L, respectively. In patients receiving RAPA/MMF, MPA AUCs ranged from 34.40 to 87.60 mg/h.L (mean, 51.07 [15.80] mg/h.L). The correlation between Co and total AUC was better than in the CsA/MMF group (r2=0.61). MPA C0 levels of 1.0 and 2.3 mg/L were correlated with AUCs of 30 and 40 mg/h.L, respectively. Statistically significant differences between RAPA/MMF and CsA/MMF were noted in the mean MMF dosage (1.90 [0.71] vs 2.87 [0.78] g/d, respectively; P<0.001), the mean dose-adjusted MPA AUC (60.95 [27.42] vs 31.92 [16.12] mg/h.L.g MMF; P<0.001), and mean dose-adjusted MPA C0 levels (5.10 [3.41] vs 1.41 [0.95] mg/L.g; P<0.001). The dose-adjusted increase to Cmax after morning dosing was comparable between groups, and there was no difference in the frequency distribution of Cmax. In the group switched from the CsA-containing regimen to the RAPA-containing regimen, the changes in MMF dose, dose-adjusted AUC, and MPA C0 levels were similar to those in the CsA/MMF and RAPA/MMF groups. CONCLUSIONS: In this comparison of measured MPA C0 levels and 12-hour MPA AUCs estimated by a limited-sampling strategy in stable heart transplant patients receiving chronic maintenance immunosuppressive therapy with CsA/MMF or RAPA/MMF, abbreviated AUC estimation predicted drug exposure more accurately than did measured C0 levels. Thus, MPA AUCs obtained by limited sampling may be useful in guiding clinical management and dosing. However, further study is required, including validation of these findings in clinical outcome studies.     

Pharmacometabonomic association of cyclophosphamide 4‐hydroxylation in hematopoietic cell transplant recipients

The widely used alkylating agent cyclophosphamide (CY) has substantive interpatient variability in the area under the curve (AUC) of it and its metabolites. Numerous factors may influence the drug‐metabolizing enzymes that metabolize CY to 4‐hydroxycyclophosphamide (4HCY), the principal precursor to CY’s cytotoxic metabolite. We sought to identify endogenous metabolomics compounds (EMCs) associated with 4HCY formation clearance (ratio of 4HCY/CY AUC) using global metabolomics. Patients who undergo hematopoietic cell transplantation receiving post‐transplant CY (PT‐CY) were enrolled, cohort 1 (n = 26) and cohort 2 (n = 25) donating longitudinal blood samples before they started HCT (pre‐HCT), before infusion of the donor allograft (pre‐graft), before the first dose of PT‐CY (pre‐CY), and 24 h after the first dose of PT‐CY (24‐h post‐CY), which is also immediately before the second dose of CY. A total of 512 and 498 EMCs were quantitated in two cohorts, respectively. Both univariate linear regression with false discovery rate (FDR), and pathway enrichment analyses using a global association test were performed. At the pre‐CY time point, no EMCs were associated at FDR less than 0.1. At pre‐HCT, cohort 1 had one EMC (levoglucosan) survive the FDR threshold. At pre‐graft, cohort 1 and cohort 2 had 20 and 13 EMCs, respectively, exhibiting unadjusted p values less than 0.05, with the only EMCs having an FDR less than 0.1 being two unknown EMCs. At 24‐h post‐CY, there were three EMCs, two ketones, and threitol, at FDR less than 0.1 in cohort 2. These results demonstrate the potential of pharmacometabonomics, but future studies in larger samples are needed to optimize CY.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

We report the first pharmacometabonomic study of the association of plasma EMCs with cyclophosphamide pharmacokinetics, specifically the ratio of 4HCY/CY AUC.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study addresses the question regarding if EMCs in the plasma before PT‐CY administration are associated with the ratio of 4HCY/CY AUC.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study adds to our knowledge that longitudinal collection of plasma EMC samples is feasible in HCT patients receiving PT‐CY. In addition, the plasma EMC changes over the ~21‐day time period that starts pre‐HCT to 24‐hr after the first PT‐CY dose.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study demonstrates the possibility of pharmacometabolomic research to evaluate the pharmacokinetics of a drug – in this case, cyclophosphamide – with a complex pharmacokinetic disposition.     

Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients

OBJECTIVE: The mutual drug-drug interaction potential of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor cerivastatin and cyclosporine (INN, ciclosporin) in kidney transplant recipients receiving individual immunosuppressive treatment was evaluated with respect to pharmacokinetic behavior of either drug and tolerability of concomitant use. METHODS: Plasma and urine concentrations of cerivastatin and its major metabolites were determined after administration of 0.2 mg single-dose cerivastatin to 12 kidney transplant recipients (9 men and 3 women) who were receiving stable individual cyclosporine treatment (mainly 200 mg twice a day). These results were compared with the single-dose pharmacokinetic results obtained from a healthy control group (n = 12, age-comparable men). Cerivastatin steady-state pharmacokinetics were evaluated in the same patients during continued immunosuppressive treatment 4 to 6 weeks later, after a 7-day treatment of 0.2 mg cerivastatin once a day. Cyclosporine steady-state concentration-time profiles were determined in blood with monoclonal (EMIT [enzyme multiplied immunoassay technique] assay, parent drug specific) and polyclonal antibodies (FPIA [fluorescence polarization immunoassay] assay, cyclosporine plus metabolites) during cerivastatin cotreatment and compared with predosing data. RESULTS: Coadministration of 0.2 mg cerivastatin once a day to the kidney transplant recipients treated with individual doses of cyclosporine and other immunosuppressive agents resulted in a 3- to 5-fold increase in cerivastatin and metabolites plasma concentrations. Cerivastatin and metabolites elimination half-lives were unaffected, and no accumulation occurred during multiple-dosing conditions. Cerivastatin had no influence on steady-state blood concentrations of cyclosporine or cyclosporine metabolites in these patients. The concomitant use of both drugs was well tolerated. CONCLUSIONS: Cerivastatin and metabolites plasma concentrations were significantly increased in kidney transplant recipients treated with cyclosporine and other immunosuppressive agents. Displacement from the main site for cerivastatin distribution-the liver-by cyclosporine-inhibited liver transport processes may explain the decrease in both metabolic clearance and volume of distribution for cerivastatin and metabolites.     

急性腹泻期间肾移植受者他克莫司血药浓度的变化

背景:长期以来器官移植工作者比较重视吗替麦考酚酯的肠道不良作用,而对他克莫司与腹泻的关系则未引起足够的关注。目的:观察肾移植受者急性腹泻期间他克莫司的谷浓度变化及对腹泻的治疗效果。方法:观察90例出现急性腹泻的肾移植受者,免疫抑制方案均为他克莫司+吗替麦考酚酯+泼尼松,检测围腹泻期间内他克莫司血药谷浓度及相关病原学指标,将浓度升高的72例患者中病原学检查阴性的48例患者分为2组,每组24例,一组在治疗过程中只减少他克莫司剂量,另一组同时减少他克莫司及吗替麦考酚酯剂量,观察对腹泻的治疗效果及他克莫司谷浓度升高持续时间。结果与结论:两种方案对腹泻的治疗效果及他克莫司谷浓度升高持续时间差异均无显著性意义。腹泻是他克莫司浓度异常升高的重要因素,腹泻期间应适当减少他克莫司剂量及增加其血药浓度监测频率,以免增加他克莫司的不良反应;在治疗过程中没有必要同时减少吗替麦考酚酯剂量,以免增加排斥发应发生率。     

The clinical validation of novel strategies for monitoring transplant recipients

In the early postoperative period after solid organ transplantation, the patient is monitored intensively to detect the early development of surgical and infectious complications or allograft rejection. Laboratory tests form an essential component of the routine monitoring protocol-particularly those that are of diagnostic value in assessing graft function. In this paper, we illustrate how a new liver-function test, alpha-glutathione S-transferase immunoassay, was subjected to systematic technical and clinical evaluation in the liver-transplant population, including a randomized, controlled trial that provided the evidence for its introduction into the routine laboratory. We also illustrate how the carefully controlled monitoring in a clinical trial is difficult to reproduce under routine circumstances and the crucial role of audit in ensuring that recommendations governing the use of a new diagnostic test are adhered to in clinical practice. Finally, we describe an "equivalence study," whereby our rigorous validation of the alpha-glutathione S-transferase assay has enabled us to fast-track the development of a simpler and cheaper liver function test (fructose 1,6-bisphosphatase), which shares similar diagnostic characteristic to alpha-glutathione S-transferase, without the requirement for a further clinical trial.