Prednisolone and Prednisone Pharmacokinetics in Adult Renal Transplant Recipients.

BACKGROUND: Prednisolone (PL) is a standard component of most immunosuppressive protocols after solid organ transplantation (Tx). Adverse effects are frequent and well known. The aim of this study was to characterize the pharmacokinetics (PKs) of PL and prednisone (PN), including cortisol (CL) and cortisone (CN) profiles, after PL treatment in renal Tx recipients in the early post-Tx phase. METHODS: This single-center, prospective, observational study included stable renal Tx recipients, >18 years of age, and in the early postengraftment phase. Blood samples were obtained predose and during a 24-hour dose interval [n = 26 samples per area under the curve (AUC0-24)], within the first 8 weeks post-Tx. PL, PN, CL, and CN concentrations were measured using high-performance liquid chromatography-tandem mass spectrometry. RESULTS: In renal Tx recipients (n = 28), our results indicated a relatively high PL exposure [median, range AUC0-24 = 3821 (2232-5382) mcg h/L], paralleled by strong suppression of endogenous CL profile, demonstrated by a low CL evening-to-morning ratio [median, range 11 (3-47)%]. A negative correlation (r = -0.83) between PL AUC0-24 and morning CL levels was observed. The best single PK variable to predict PL AUC0-24 was PL C6 (r2 = 0.82). An algorithm based on 3 PK sampling time points: trough, 2, and 4 hours after PL dosing, predicted PL AUC0-24 with a low percentage prediction error (PPE = 5.2 ± 1.5%) and a good correlation of determination (r2 = 0.91). PL AUC0-24 varied 3-fold among study participants, whereas CL AUC0-24 varied by 18-fold. CONCLUSIONS: The large interindividual variability in both PL exposure and suppression of endogenous CL implies a possible role for therapeutic drug monitoring. An abbreviated profile within the first 4 hours after PL dosing provides a good prediction of PL exposure in renal Tx recipients. The strong negative correlation between PL AUC0-24 and morning CL levels suggests a possible surrogate marker for drug exposure for further evaluation.

Physiologically Based Pharmacokinetic Modeling Involving Nonlinear Plasma and Tissue Binding: Application to Prednisolone and Prednisone in Rats.

The pharmacokinetics (PK) of prednisolone (PNL) exhibit nonlinearity related to plasma protein binding, tissue binding, metabolic interconversion with prednisone (PN), and renal elimination. Blood and 11 tissues were collected from male Wistar rats after steady-state (SS) infusion and after subcutaneous boluses of 50 mg/kg of PNL. Concentrations of PNL and PN were measured by liquid chromatography-tandem mass spectrometry. Plasma and tissue profiles were described using a complex physiologically based pharmacokinetics (PBPK) model. Concentrations of PN and PNL were in rapid equilibrium in plasma and tissues. The tissue partition coefficients (K p ) of PNL calculated from most subcutaneously dosed tissue and plasma areas were similar to SS infusion and in silico values. The blood-to-plasma ratio of PNL was 0.71 with similar red blood cell and unbound-plasma concentrations. Plasma protein binding (60%-90%) was related to corticosteroid-binding globulin (CBG) saturation. Tissue distribution was nonlinear. The equilibrium dissociation constant (K d ) of PNL shared by all tissues was 3.01 ng/ml, with the highest binding in muscle, followed by liver, heart, intestine, and bone and the lowest binding in skin, spleen, fat, kidney, lung, and brain. Fat and bone distribution assumed access only to interstitial space. Brain PNL concentrations (K p = 0.05) were low owing to presumed P-glycoprotein-mediated efflux. Clearances of CBG-free PNL were 1789 from liver and 191.2 ml/h from kidney. The PN/PNL ratio was nonlinear for plasma, spleen, heart, intestine, bone, fat, and linear for the remaining tissues. Our PBPK model with multiple complexities well described the PK profiles of PNL and PN in blood, plasma, and diverse tissues. SIGNIFICANCE STATEMENT: Because steroids, such as prednisolone and prednisone, have similar and complex pharmacokinetics properties in various species, receptors in most tissues, and multiple therapeutic and adverse actions, this physiologically based pharmacokinetics (PBPK) model may provide greater insights into the pharmacodynamic complexities of corticosteroids. The complex properties of these compounds require innovative PBPK modeling approaches that may be instructive for other therapeutic agents.

Population pharmacokinetics of mycophenolic acid in Mexican patients with lupus nephritis.

BACKGROUND: Mycophenolic acid (MPA) is an effective oral immunosuppressive drug used to treat lupus nephritis (LN), which exhibits large pharmacokinetic variability. This study aimed to characterize MPA pharmacokinetic behaviour in Mexican LN patients and to develop a population pharmacokinetic model which identified factors that influence MPA pharmacokinetic variability. METHODS: Blood samples from LN patients treated with mycophenolate mofetil (MMF) were collected pre dose and up to six hours post dose. MPA concentrations were determined by a validated ultra-performance liquid chromatography tandem mass spectrometry technique. Patients were genotyped for polymorphisms in enzymes (UGT1A8, 1A9 and 2B7) and transporters (ABCC2 and SLCO1B3). The anthropometric, clinical, genetic and co-medication characteristics of each patient were considered as potential covariates to explain the variability. RESULTS: A total of 294 MPA concentrations from 40 LN patients were included in the development of the model. The data were analysed using NONMEM software and were best described by a two-compartment linear model. MPA CL, Vc, Vp, Ka and Q were 15.4 L/h, 22.86 L, 768 L, 1.28 h-1 and 20.3 L/h, respectively. Creatinine clearance and prednisone co-administration proved to have influence on clearance, while body weight influenced Vc. The model was internally validated, proving to be stable. MMF dosing guidelines were obtained through stochastic simulations performed with the final model. CONCLUSIONS: This is the first MPA population pharmacokinetic model to have found that co-administration of prednisone results in a considerable increase on clearance. Therefore, this and the other covariates should be taken into account when prescribing MMF in order to optimize the immunosuppressant therapy in patients with LN.

Learning pharmacokinetic models for in vivo glucocorticoid activation.

To understand trends in individual responses to medication, one can take a purely data-driven machine learning approach, or alternatively apply pharmacokinetics combined with mixed-effects statistical modelling. To take advantage of the predictive power of machine learning and the explanatory power of pharmacokinetics, we propose a latent variable mixture model for learning clusters of pharmacokinetic models demonstrated on a clinical data set investigating 11ß-hydroxysteroid dehydrogenase enzymes (11ß-HSD) activity in healthy adults. The proposed strategy automatically constructs different population models that are not based on prior knowledge or experimental design, but result naturally as mixture component models of the global latent variable mixture model. We study the parameter of the underlying multi-compartment ordinary differential equation model via identifiability analysis on the observable measurements, which reveals the model is structurally locally identifiable. Further approximation with a perturbation technique enables efficient training of the proposed probabilistic latent variable mixture clustering technique using Estimation Maximization. The training on the clinical data results in 4 clusters reflecting the prednisone conversion rate over a period of 4 h based on venous blood samples taken at 20-min intervals. The learned clusters differ in prednisone absorption as well as prednisone/prednisolone conversion. In the discussion section we include a detailed investigation of the relationship of the pharmacokinetic parameters of the trained cluster models for possible or plausible physiological explanation and correlations analysis using additional phenotypic participant measurements.

Experience with generic pegylated L-asparaginase in children with acute lymphoblastic leukemia and monitoring of serum asparaginase activity.

BACKGROUND: Pegylated asparaginase (P-Asp) though integral to acute lymphoblastic leukemia (ALL) therapy is often not accessible to patients in developing countries. We share our clinical experience with generic P-Asp along with monitoring of asparaginase activity. METHODS: In this prospective observational study, patients ≤18 years of age with ALL were assigned to receive either generic P-Asp or native asparaginase (N-Asp) in a non-randomized manner. Treatment protocol was based on ALL BFM-95 backbone. The dose of P-Asp was 1500 IU/m2 by intravenous route during induction (Ia) and re-induction (IIa) phase of therapy. RESULTS: N-Asp or P-Asp was administered to 52 and 54 of the 106 eligible patients respectively. Demographic and disease characteristics were comparable in both arms. The mean trough levels for N-Asp and P-Asp were 156.87 ± 22.35 IU/L and 216.03 ± 73.40 IU/L, respectively (p value <0.001) and all patients achieved therapeutic levels during Ia. Incidence of asparaginase-attributable toxicity was similar in the two arms in both phases of treatment, although hospitalization due to noninfectious causes was more common in P-Asp arm during Ia (13% versus 0%, p value, 0.01). Clinical hypersensitivity and silent inactivation were not observed during Ia while these occurred in 13% and 5% of patients in the N-Asp arm and P-Asp arms of IIa, respectively. The 2-year event free survival for P-Asp and N-Asp groups was 84% and 80.7%, respectively (p value 0.85). CONCLUSION: Generic P-Asp was observed to be efficacious and well tolerated in our patients and adequate therapeutic levels were sustained for 2 weeks.

The pharmacokinetics of cytarabine administered subcutaneously, combined with prednisone, in dogs with meningoencephalomyelitis of unknown etiology.

The objective of this study was to describe the pharmacokinetics (PK) of cytarabine (CA) after subcutaneous (SC) administration to dogs with meningoencephalomyelitis of unknown etiology (MUE). Twelve dogs received a single SC dose of CA at 50 mg/m2 as part of treatment of MUE. A sparse sampling technique was used to collect four blood samples from each dog from 0 to 360 min after administration. All dogs were concurrently receiving prednisone (0.5-2 mg kg-1 day-1 ). Plasma CA concentrations were measured by HPLC, and pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling (NLME). Plasma drug concentrations ranged from 0.05 to 2.8 µg/ml. The population estimate (CV%) for elimination half-life and Tmax of cytarabine in dogs was 1.09 (21.93) hr and 0.55 (51.03) hr, respectively. The volume of distribution per fraction absorbed was 976.31 (10.85%) ml/kg. Mean plasma concentration of CA for all dogs was above 1.0 µg/ml at the 30-, 60-, 90-, and 120-min time points. In this study, the pharmacokinetics of CA in dogs with MUE after a single 50 mg/m2 SC injection in dogs was similar to what has been previously reported in healthy beagles; there was moderate variability in the population estimates in this clinical population of dogs.

Prednisolone and Prednisone Pharmacokinetics in Pediatric Renal Transplant Recipients-A Prospective Study.

BACKGROUND: Prednisolone is a standard component of immunosuppressive protocols in renal transplantation (Tx) and despite standardized treatment regimens, adverse side effects are still frequent. The aim of this study was to characterize the pharmacokinetics of prednisolone and prednisone in pediatric renal transplant recipients in the first 52 weeks post Tx, to describe the relationship between prednisolone and prednisone, and to investigate a possible relationship between the development of new-onset diabetes after Tx (NODAT) and glucocorticoid exposure. METHODS: Renal transplant recipients receiving prednisolone (n = 11, age 1-15 years) were included in this prospective open-label, descriptive, nonrandomized, and noninterventional study. Blood samples were drawn pre-Tx and during selected dose intervals (0, 1, 2, 4, 6, and 12 hours postdose; less frequent in children <10 kg) at 1, 2, 3, 4, 12, and 52 weeks post-Tx. Concentrations of prednisolone and cortisol, their inactive keto forms, plus methylprednisolone, were measured using a validated LC-MS/MS method. Genetic variants in the CYP3A4, CYP3A5, ABCB1, and HSD11B2 genes were analyzed using real-time polymerase chain reaction and Sanger sequencing. Correlation with NODAT was investigated. RESULTS: The patients displayed considerable intra- and inter-individual variability in prednisolone exposure, with up to 5-fold differences in the area under the concentration-time curve (AUC). There were up to 7-fold differences in prednisolone/prednisone AUC ratio between patients, and patients experiencing NODAT tended to have a higher ratio (>12) compared with patients without NODAT (<12). Genetic variants in CYP3A5 and ABCB1 were found, but due to the limited study population causality cannot be definitive. CONCLUSIONS: The study suggests that a high prednisolone/prednisone AUC ratio may be a possible risk factor for NODAT. Further studies of individualization of glucocorticoid treatment in pediatric organ Tx are warranted.

Associations of HSD11B1 polymorphisms with tacrolimus concentrations in Chinese renal transplant recipients with prednisone combined therapy.

Tacrolimus requires close therapeutic drug monitoring because of its narrow therapeutic index and marked interindividual pharmacokinetic variation. In this study, we investigated the associations of polymorphisms in the gene encoding 11ß-hydroxysteroid dehydrogenase type 1 (HSD11B1) with tacrolimus concentrations in Chinese renal transplant recipients during the early posttransplantation stage. A total of 258 renal transplant recipients receiving tacrolimus with prednisone (30 mg) combined therapy were genotyped for HSD11B1 rs846908, rs846910, rs4844880, and CYP3A5*3 polymorphisms. Tacrolimus trough concentrations were determined on days 6-9 after transplantation, measured by a chemiluminescent microparticle immunoassay. Among the CYP3A5 expressers, the dose-adjusted trough concentration (C0/D) of tacrolimus in HSD11B1 rs846908 AA homozygous individuals was considerably lower than found in GG+GA carriers [56.2 (23.9-86.6) versus 76.7 (12.6-220.0) (ng/ml)/(mg/kg), P = 0.0204]; HSD11B1 rs846910 AA homozygotes had a lower tacrolimus C0/D compared with GG+GA carriers [51.2 (23.9-86.6) versus 76.3 (12.6-220.0) (ng/ml)/(mg/kg), P = 0.0367]; carriers with the HSD11B1 rs4844880 AA genotype had a significantly lower tacrolimus C0/D with respect to carriers of TT+TA genotypes [61.3 (23.9-97.5) versus 77.2 (12.6-220.0) (ng/ml)/(mg/kg), P = 0.0002]; the HSD11B1 AA-AA-AA haplotype carriers had a lower tacrolimus C0/D than noncarriers [51.2 (23.9-86.6) versus 76.3 (12.6-220.0) (ng/ml)/(mg/kg), P = 0.0367]. These findings illustrate that the HSD11B1 genotypes are closely correlated with tacrolimus trough concentrations, suggesting that these polymorphisms may be useful for safer dosing of tacrolimus.

About the Therapy of Laryngotracheitis (Croup): Significance of Rectal Dosage Forms.

Glucocorticoids are drugs of choice for treatment of laryngotracheitis (croup). They may be administered orally as tablets or juice, locally as inhalation or rectally as suppository or capsule. If doctors decide to use a rectal administration for practical reasons, it is obvious from a pharmacokinetic and pharmacodynamic point of view that prednisolone capsules have an earlier and stronger anti-inflammatory effect than a prednisone suppository.

Pharmacokinetics of total and unbound prednisone and prednisolone in stable kidney transplant recipients with diabetes mellitus.

BACKGROUND: The corticosteroid prednisone is an important component of posttransplantation immunosuppressive therapy. Pharmacokinetic parameters of prednisone or its pharmacologically active metabolite, prednisolone, are not well characterized in transplant recipients. The objective of this study was to compare the pharmacokinetics of total and unbound prednisone and prednisolone in diabetic and nondiabetic stable kidney transplant recipients and to evaluate the factors influencing plasma protein binding of prednisolone. METHODS: Prednisone and prednisolone concentration-time profiles were obtained in 20 diabetic and 18 nondiabetic stable kidney transplant recipients receiving an oral dose of 5-10 mg prednisone per day. In addition to drug and metabolite exposures, factors influencing prednisolone protein binding were evaluated using a nonlinear mixed-effects modeling approach. This model takes into account the binding of prednisolone and cortisol to corticosteroid-binding globulin (CBG) in a saturable fashion and binding of prednisolone to albumin in a nonsaturable fashion. Finally, we have investigated the influence of several covariates including diabetes, glucose concentration, hemoglobin A1c, creatinine clearance, body mass index, gender, age, and time after transplantation on the affinity constant (K) between corticosteroids and their binding proteins. RESULTS: In patients with diabetes, the values of dose-normalized area under the concentration-time curves were 27% and 23% higher for total and unbound prednisolone, respectively. Moreover, the ratio of total prednisolone to prednisone concentrations (active/inactive forms) was higher in diabetic subjects (P < 0.001). Modeling protein binding results revealed that the affinity constant of corticosteroid-binding globulin-prednisolone (KCBG,PL) was related to the patient's gender and diabetes status. CONCLUSIONS: Higher prednisolone exposure could potentially lead to the increased risk of corticosteroid-related complications in diabetic kidney transplant recipients.

What do we know about steroids metabolism and 'PK/PD approach' in AKI and CKD especially while on RRT--current status in 2014.

The knowledge on PK behavior of steroid drugs such as prednisolone or prednisone has indeed been expanding but at a rather slow pace. First, convenient, rapid, and specific determination of plasma levels of these steroids was largely indebted to the breakthrough of high performance liquid chromatography (HPLC). Second, prednisolone is non-linearly protein-bound. Since unbound prednisolone is the biologically active compound, only the measurement of this free fraction in plasma is relevant. Third, the short half-life of prednisolone precludes to reach steady-state levels and requires determination of the area under the concentration-time curve. Fourth, prednisolone and prednisone are mutually convertible. Intravenous prednisolone, however, is administered as a pro-drug ester, which renders comparison and interpretation of reported PK data of both agents unreliable. A poignant lack of awareness and knowledge regarding catabolism, clearance mechanisms, and elimination route of steroids fuels the ongoing controversy that surrounds adjunctive corticosteroid therapy in patients with chronic or acute inflammatory disease. This particular patient population is also more prone to develop early and significant kidney dysfunction, necessitating extra-renal support. A better understanding of steroid PK/PD, preferentially guided by HPLC measurement of plasma steroid concentrations, likely will have direct clinical implications, for instance by adapting steroid doses in IHD or implementing higher dose regimens during CRRT.

Demonstrating Bioequivalence for Two Dose Strengths of Niraparib and Abiraterone Acetate Dual-Action Tablets Versus Single Agents: Utility of Clinical Study Data Supplemented with Modeling and Simulation.

BACKGROUND AND OBJECTIVE: The combination of niraparib and abiraterone acetate (AA) plus prednisone is under investigation for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and metastatic castration-sensitive prostate cancer (mCSPC). Regular-strength (RS) and lower-strength (LS) dual-action tablets (DATs), comprising niraparib 100 mg/AA 500 mg and niraparib 50 mg/AA 500 mg, respectively, were developed to reduce pill burden and improve patient experience. A bioequivalence (BE)/bioavailability (BA) study was conducted under modified fasting conditions in patients with mCRPC to support approval of the DATs. METHODS: This open-label randomized BA/BE study (NCT04577833) was conducted at 14 sites in the USA and Europe. The study had a sequential design, including a 21-day screening phase, a pharmacokinetic (PK) assessment phase comprising three periods [namely (1) single-dose with up to 1-week run-in, (2) daily dose on days 1-11, and (3) daily dose on days 12-22], an extension where both niraparib and AA as single-agent combination (SAC; reference) or AA alone was continued from day 23 until discontinuation, and a 30-day follow-up phase. Patients were randomly assigned in a parallel-group design (four-sequence randomization) to receive a single oral dose of niraparib 100 mg/AA 1000 mg as a LS-DAT or SAC in period 1, and patients continued as randomized into a two-way crossover design during periods 2 and 3 where they received niraparib 200 mg/AA 1000 mg once daily as a RS-DAT or SAC. The design was powered on the basis of crossover assessment of RS-DAT versus SAC. During repeated dosing (periods 2 and 3, and extension phase), all patients also received prednisone/prednisolone 5 mg twice daily. Plasma samples were collected for measurement of niraparib and abiraterone plasma concentrations. Statistical assessment of the RS-DAT and LS-DAT versus SAC was performed on log-transformed pharmacokinetic parameters data from periods 2 and 3 (crossover) and from period 1 (parallel), respectively. Additional paired analyses and model-based bioequivalence assessments were conducted to evaluate the similarity between the LS-DAT and SAC. RESULTS: For the RS-DAT versus SAC, the 90% confidence intervals (CI) of geometric mean ratios (GMR) for maximum concentration at a steady state (Cmax,ss) and area under the plasma concentration-time curve from 0-24 h at a steady state (AUC 0-24h,ss) were respectively 99.18-106.12% and 97.91-104.31% for niraparib and 87.59-106.69 and 86.91-100.23% for abiraterone. For the LS-DAT vs SAC, the 90% CI of GMR for AUC0-72h of niraparib was 80.31-101.12% in primary analysis, the 90% CI of GMR for Cmax,ss and AUC 0-24h,ss of abiraterone was 85.41-118.34% and 86.51-121.64% respectively, and 96.4% of simulated LS-DAT versus SAC BE trials met the BE criteria for both niraparib and abiraterone. CONCLUSIONS: The RS-DAT met BE criteria (range 80%-125%) versus SAC based on 90% CI of GMR for Cmax,ss and AUC 0-24h,ss. The LS-DAT was considered BE to SAC on the basis of the niraparib component meeting the BE criteria in the primary analysis for AUC 0-72h; abiraterone meeting the BE criteria in additional paired analyses based on Cmax,ss and AUC 0-24h,ss; and the percentage of simulated LS-DAT versus SAC BE trials meeting the BE criteria for both. GOV IDENTIFIER: NCT04577833.

Population pharmacokinetics and exposure-response analyses of polatuzumab vedotin in patients with previously untreated DLBCL from the POLARIX study.

Polatuzumab vedotin is a CD79b-directed antibody-drug conjugate that targets B cells and delivers the cytotoxic payload monomethyl auristatin E (MMAE). The phase III POLARIX study (NCT03274492) evaluated polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) as first-line treatment of diffuse large B-cell lymphoma (DLBCL). To examine dosing decisions for this regimen, population pharmacokinetic (popPK) analysis, using a previously developed popPK model, and exposure-response (ER) analysis, were performed. The popPK analysis showed no clinically meaningful relationship between cycle 6 (C6) antibody-conjugated (acMMAE)/unconjugated MMAE area under the concentration-time curve (AUC) or maximum concentration, and weight, sex, ethnicity, region, mild or moderate renal impairment, mild hepatic impairment, or other patient and disease characteristics. In the ER analysis, C6 acMMAE AUC was significantly associated with longer progression-free and event-free survival (both p = 0.01). An increase of <50% in acMMAE/unconjugated MMAE exposure did not lead to a clinically meaningful increase in adverse events of special interest. ER data and the benefit-risk profile support the use of polatuzumab vedotin 1.8 mg/kg once every 3 weeks with R-CHP for six cycles in patients with previously untreated DLBCL.

Formation of threohydrobupropion from bupropion is dependent on 11ß-hydroxysteroid dehydrogenase 1.

Bupropion is widely used for treatment of depression and as a smoking-cessation drug. Despite more than 20 years of therapeutic use, its metabolism is not fully understood. While CYP2B6 is known to form hydroxybupropion, the enzyme(s) generating erythro- and threohydrobupropion have long remained unclear. Previous experiments using microsomal preparations and the nonspecific inhibitor glycyrrhetinic acid suggested a role for 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) in the formation of both erythro- and threohydrobupropion. 11ß-HSD1 catalyzes the conversion of inactive glucocorticoids (cortisone, prednisone) to their active forms (cortisol, prednisolone). Moreover, it accepts several other substrates. Here, we used for the first time recombinant 11ß-HSD1 to assess its role in the carbonyl reduction of bupropion. Furthermore, we applied human, rat, and mouse liver microsomes and a selective inhibitor to characterize species-specific differences and to estimate the relative contribution of 11ß-HSD1 to bupropion metabolism. The results revealed 11ß-HSD1 as the major enzyme responsible for threohydrobupropion formation. The reaction was stereoselective and no erythrohydrobupropion was formed. Human liver microsomes showed 10 and 80 times higher activity than rat and mouse liver microsomes, respectively. The formation of erythrohydrobupropion was not altered in experiments with microsomes from 11ß-HSD1-deficient mice or upon incubation with 11ß-HSD1 inhibitor, indicating the existence of another carbonyl reductase that generates erythrohydrobupropion. Molecular docking supported the experimental findings and suggested that 11ß-HSD1 selectively converts R-bupropion to threohydrobupropion. Enzyme inhibition experiments suggested that exposure to bupropion is not likely to impair 11ß-HSD1-dependent glucocorticoid activation but that pharmacological administration of cortisone or prednisone may inhibit 11ß-HSD1-dependent bupropion metabolism.

A phase I study of everolimus and CHOP in newly diagnosed peripheral T-cell lymphomas.

BACKGROUND: We performed a phase I study to determine the dose and safety of everolimus as a combination chemotherapy in peripheral T-cell lymphoma (PTCL). METHODS: Four dose levels (2.5 to 10 mg) of everolimus from days 1 to 14 with CHOP (750 mg/m(2) cyclophosphamide, 50 mg/m(2) doxorubicin, and 1.4 mg/m(2) (maximum 2 mg) vincristine on day 1, and 100 mg/day prednisone on days 1 to 5) every 21 days were planned. RESULTS: Fifteen patients newly diagnosed with stage III/IV PTCL were enrolled. One of 6 patients at dose level 2 (5 mg everolimus) had grade 3 hepatotoxicity and 3 of 6 patients at level 3 (7.5 mg everolimus) had grade 4 hematologic toxicities (two grade 4 thrombocytopenia and one grade 4 neutropenia with fever lasting more than 3 days). The recommended dose of everolimus for combination was 5 mg. There were no differences in steady state trough concentrations of everolimus between cycles 1 and 2 for all three dose levels. All evaluable patients achieved response (8 complete and 6 partial). CONCLUSIONS: Everolimus (5 mg) can be safely combined with CHOP leading to a feasible and effective regimen for PTCL. The subsequent phase II is now in progress.

Intracellular IFN-γ and IL-2 expression monitoring as surrogate markers of the risk of acute rejection and personal drug response in de novo liver transplant recipients.

Biomarker monitoring is needed in transplantation to reflect individual response to immunosuppressive drugs and graft outcome. We evaluated intracellular expression and soluble production of interferon-(IFN)-γ and interleukin-(IL)-2 as predictive biomarkers of acute rejection (AR) and personal drug response. Pharmacokinetic-pharmacodynamic profiles were determined in 47 de novo liver recipients treated with tacrolimus, mycophenolate mofetil and prednisone. Of the 47 patients, AR occurred in nine. There were no differences in drug concentrations between rejectors and non-rejectors. A pre-transplantation cut-off value of 55.80% for %CD8(+)-IFN-γ(+) identified patients at high risk of AR with a sensitivity of 75% and a specificity of 82%. In the first week post-transplantation, patients with a % inhibition for soluble IFN-γ, %CD8(+)-IFN-γ(+) and %CD8(+)-IL2(+) lower than 40% developed AR, showing low susceptibility to immunosuppressive drugs. Therefore, effector-T-cell response monitoring may help physicians to identify personal response to treatment and patients at high risk of AR.

Monitoring prednisolone and prednisone in saliva: a population pharmacokinetic approach in healthy volunteers.

BACKGROUND: Prednisolone (PLN) is a widely used corticosteroid in a variety of immune-mediated diseases. Treatment regimes generally consist of empirically derived treatment doses, whereas therapeutic response among patients is highly variable. Drug monitoring of serum PLN levels might support a more rational approach to dose selection, yet is invasive and laborious. In analogy to cortisol, salivary PLN may offer a good alternative for serum PLN, being a representative approximation of free serum PLN. The aims of this study were to evaluate the correlation between free serum and salivary PLN levels and to quantify this relationship within a population pharmacokinetic model. METHODS: PLN and prednisone (PN) concentrations were measured in 396 samples from 19 healthy volunteers after oral ingestion of 80 mg PLN. Measurements in serum, ultrafiltrate, and saliva were performed with a recently validated liquid chromatography tandem mass spectrometry method. Population pharmacokinetic analysis was performed with nonlinear mixed effect modeling using NONMEM. RESULTS: Salivary PLN levels correlated well with free serum PLN levels (r = 0.931, P < 0.01). A weaker correlation was found for PN (r = 0.318, P < 0.01), which may be explained by the finding that salivary PN levels mainly seemed to consist of PLN enzymatically converted to PN. Total and free serum PLN concentrations decreased over time after drug administration and showed a nonlinear mutual relationship, consistent with concentration-dependent protein binding. Modeled PLN pharmacokinetics corresponded with previous reports. Low to moderate interindividual variability was found for V/F and CL/F (coefficients of variation were 13.8% and 14.6%, respectively). Free and salivary PLN showed a nonlinear relationship with total PLN. An equation predicting free serum levels from salivary levels was successfully derived from the data. CONCLUSIONS: This study is the first to describe the relationship between salivary and (free) serum PLN using a population pharmacokinetic model. Salivary PLN was found to be a reliable predictor of free and total serum PLN in healthy volunteers. The results of this study encourage further exploration of the use of saliva as a noninvasive and feasible method for drug monitoring of PLN.

Differential drug retention between anti-TNF agents and alternative biological agents after inadequate response to an anti-TNF agent in rheumatoid arthritis patients.

BACKGROUND: After inadequate response to an antitumour necrosis factor (aTNF) agent for treatment of rheumatoid arthritis (RA), rheumatologists can choose an alternative aTNF or a biological agent with another mode of action (non-aTNF biological (non-aTNF-Bio)). OBJECTIVE: To compare drug retention rates of non-aTNF-Bio with alternative aTNF. METHODS: All patients within the Swiss RA cohort (SCQM-RA) treated with an alternative biotherapy after a prior inadequate response to aTNF were analysed. The drug retention of alternative aTNF was compared with non-aTNF-Bio using Cox proportional hazards models, adjusted for potential confounders. RESULTS: 1485 treatment courses after aTNF failure were available for analysis, 853 with alternative aTNF and 632 with non-aTNF-Bio. The median drug retention was 32 months (IQR 14-54) on non-aTNF-Bio versus 21 months (IQR 8-53) on alternative aTNF, or a 50% reduction drug discontinuation risk in favour of non-aTNF-Bio (adjusted hazard ratio (HR) for non-aTNF-Bio: 0.50 (95% CI 0.41 to 0.62)). This effect appears to be modified by the type of prior aTNF failure, with a larger difference in favour of non-aTNF-Bio in patients having experienced a primary failure with a previous aTNF (HR: 0.33 (95% CI 0.24 to 0.47), p<0.001). CONCLUSION: After inadequate response to aTNF, and particularly after primary failure, patients on a non-aTNF-Bio agent have significantly higher drug retention rates.

The pharmacokinetics of prednisolone and prednisone in adult liver transplant recipients early after transplantation.

BACKGROUND: Glucocorticoids represent a cornerstone in the immunosuppressive therapy after solid organ transplantation. Interconversion between active and inactive states of glucocorticoids (ie, prednisolone and prednisone) is catalyzed by the enzymes 11ß-hydroxysteroid dehydrogenases 1 and 2. MATERIALS: This study investigated the pharmacokinetics of prednisolone and prednisone in 16 liver transplant recipients. Blood samples were collected in four 12-hour dosing intervals during the first 3 weeks posttransplant, including samples drawn at 13 time points. RESULTS: Area under the time-concentration curve of prednisolone was 3-13 µg·h·mL·mg·kg with maximum concentrations (Cmax) between 0.37 and 2.5 µg·mL·mg·kg and trough concentrations (C0) between 0.13 and 1.1 µg·mL·mg·kg. The elimination half-lives were 1.9-10.3 hours. Apparent volume of distribution (VD/F) and apparent clearance (Cl/F) were 23-159 L and 4.7-28.7 L/h, respectively. CONCLUSIONS: This study demonstrated large intraindividual and interindividual variabilities in glucocorticoid pharmacokinetics. The results suggest that current prednisolone dosing early after liver transplantation might be too high, in particular when coadministered with methylprednisolone. These findings indicate a potential for improvement by personalized dosing of glucocorticoids in organ transplantation.

Determination of unbound prednisolone, prednisone and cortisol in human serum and saliva by on-line solid-phase extraction liquid chromatography tandem mass spectrometry and potential implications for drug monitoring of prednisolone and prednisone in saliva.

Prednisolone (PLN) and prednisone (PN) are widely used glucocorticoids. Drug monitoring of PLN and PN is not routinely done owing to the need for multiple blood sampling and challenging measurement of unbound PLN and PN in blood. Here we present a robust method for quantification of cortisol, PLN and PN in serum, ultrafiltrate and saliva by on-line solid-phase extraction LC-MS/MS. The method is linear for the three analytes over the range of 6-1400 nmol/L for serum and 2-450 nmol/L for ultrafiltrate and saliva. Within-run precision of all three analytes was <10% and total precision was <15%. This method was applied to create time-concentration profiles of cortisol, PLN and PN after an oral dose of prednisolone in a healthy volunteer. Salivary levels of PLN correlated well with ultrafiltrate levels (p < 0.01), while this correlation was only marginal for PN (p = 0.052). The PN/PLN ratio was significantly higher in saliva than in ultrafiltrate and serum (p < 0.01). Addition sums of both metabolites in saliva showed excellent correlation with those of ultrafiltrate (p < 0.01). These findings have not been presented before and may have important implications for future studies concerning drug monitoring of PLN and PN in saliva.