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.

Mechanistic physiology-based pharmacokinetic modeling to elucidate vincristine-induced peripheral neuropathy following treatment with novel kinase inhibitors.

PURPOSE: Limited information is available regarding the drug-drug interaction (DDI) potential of molecular targeted agents and rituximab plus cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), and prednisone (R-CHOP) therapy. The addition of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib to R-CHOP therapy results in increased toxicity versus R-CHOP alone, including higher incidence of peripheral neuropathy. Vincristine is a substrate of P-glycoprotein (P-gp, ABCB1); drugs that inhibit P-gp could potentially cause increased toxicity when co-administered with vincristine through DDI. While the combination of the BTK inhibitor acalabrutinib and R-CHOP is being explored clinically, the DDI potential between these therapies is unknown. METHODS: A human mechanistic physiology-based pharmacokinetic (PBPK) model of vincristine following intravenous dosing was developed to predict potential DDI interactions with combination therapy. In vitro absorption, distribution, metabolism, and excretion and in vivo clinical PK parameters informed PBPK model development, which was verified by comparing simulated vincristine concentrations with observed clinical data. RESULTS: While simulations suggested no DDI between vincristine and ibrutinib or acalabrutinib in plasma, simulated vincristine exposure in muscle tissue was increased in the presence of ibrutinib but not acalabrutinib. Extrapolation of the vincristine mechanistic PBPK model to other P-gp substrates further suggested DDI risk when ibrutinib (area under the concentration-time curve [AUC] ratio: 1.8), but not acalabrutinib (AUC ratio: 0.92), was given orally with venetoclax or digoxin. CONCLUSION: Overall, these data suggest low DDI risk between acalabrutinib and P-gp substrates with negligible increase in the potential risk of vincristine-induced peripheral neuropathy when acalabrutinib is added to R-CHOP therapy.

Evaluation for pharmacokinetic exposure of cytotoxic anticancer drugs in elderly patients receiving (R-)CHOP therapy.

(R-)miniCHOP therapy, which delivers approximately half-doses of the (R-)CHOP regimen, has shown efficacy and safety in patients who are more than 80 years old. This study aimed to compare the area under the plasma concentration-time curves (AUCs) of vincristine (VCR), doxorubicin (DXR), and cyclophosphamide (CPA) between (R-)CHOP and (R-)miniCHOP regimens. The AUCs were compared between patients aged 65-79 years receiving (R-)CHOP therapy and those aged 80 years and older receiving (R-)miniCHOP therapy. Age was not an independent variable for predicting the dose-adjusted AUCs (AUC/Ds) of cytotoxic anticancer drugs. The median AUCs of DXR and CPA were significantly smaller in the (R-)miniCHOP group than in the (R-)CHOP group (168.7 vs. 257.9 ng h/mL, P = 0.003, and 219.9 vs. 301.7 µg h/mL, P = 0.020, respectively). The median AUCs of VCR showed the same trend but the difference was not significant (24.83 vs. 34.85 ng h/mL, P = 0.135). It is possible that the AUCs of VCR, DXR, and CPA in patients aged 80 years and older receiving (R-)miniCHOP therapy may be lower than those in patients 65-79 years old receiving (R-)CHOP therapy.

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.

Pharmacokinetics, Safety, and Antitumor Effect of Apalutamide with Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer: Phase Ib Study.

PURPOSE: Apalutamide is a next-generation androgen receptor (AR) inhibitor approved for patients with nonmetastatic castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer. We evaluated the pharmacokinetics, safety, and antitumor activity of apalutamide combined with abiraterone acetate plus prednisone (AA-P) in patients with metastatic CRPC (mCRPC). PATIENTS AND METHODS: Multicenter, open-label, phase Ib drug-drug interaction study conducted in 57 patients with mCRPC treated with 1,000 mg abiraterone acetate plus 10 mg prednisone daily beginning on cycle 1 day 1 (C1D1) and 240 mg apalutamide daily starting on C1D8 in 28-day cycles. Serial blood samples for pharmacokinetic analysis were collected on C1D7 and C2D8. RESULTS: Systemic exposure to abiraterone, prednisone, and prednisolone decreased 14%, 61%, and 42%, respectively, when apalutamide was coadministered with AA-P. No increase in mineralocorticoid excess-related adverse events was observed. Patients without prior exposure to AR signaling inhibitors had longer median treatment duration and greater mean decrease in prostate-specific antigen (PSA) from baseline compared with those who had received prior therapy. Confirmed PSA reductions of ≥50% from baseline at any time were observed in 80% (12/15) of AR signaling inhibitor-naïve patients and 14% (6/42) of AR signaling inhibitor-treated patients. CONCLUSIONS: Treatment with apalutamide plus AA-P was well tolerated and showed evidence of antitumor activity in patients with mCRPC, including those with disease progression on AR signaling inhibitors. No clinically significant pharmacokinetic interaction was observed between abiraterone and apalutamide; however, apalutamide decreased exposure to prednisone. These data support development of 1,000 mg abiraterone acetate plus 10 mg prednisone daily with 240 mg apalutamide daily in patients with mCRPC.

Pharmacokinetics of polatuzumab vedotin in combination with R/G-CHP in patients with B-cell non-Hodgkin lymphoma.

PURPOSE: The phase Ib/II open-label study (NCT01992653) evaluated the antibody-drug conjugate polatuzumab vedotin (pola) plus rituximab/obinutuzumab, cyclophosphamide, doxorubicin, and prednisone (R/G-CHP) as first-line therapy for B-cell non-Hodgkin lymphoma (B-NHL). We report the pharmacokinetics (PK) and drug-drug interaction (DDI) for pola. METHODS: Six or eight cycles of pola 1.0-1.8 mg/kg were administered intravenously every 3 weeks (q3w) with R/G-CHP. Exposures of pola [including antibody-conjugated monomethyl auristatin E (acMMAE) and unconjugated MMAE] and R/G-CHP were assessed by non-compartmental analysis and/or descriptive statistics with cross-cycle comparisons to cycle 1 and/or after multiple cycles. Pola was evaluated as a potential victim and perpetrator of a PK drug-drug interaction with R/G-CHP. Population PK (popPK) analysis assessed the impact of prior treatment status (naïve vs. relapsed/refractory) on pola PK. RESULTS: Pola PK was similar between treatment arms and independent of line of therapy. Pola PK was dose proportional from 1.0 to 1.8 mg/kg with R/G-CHP. Geometric mean volume of distribution and clearance of acMMAE ranged from 57.3 to 95.6 mL/kg and 12.7 to 18.2 mL/kg/day, respectively. acMMAE exhibited multi-exponential decay (elimination half-life ~ 1 week). Unconjugated MMAE exhibited formation rate-limited kinetics. Exposures of pola with R/G-CHP were similar to those in the absence of CHP; exposures of R/G-CHP in the presence of pola were comparable to those in the absence of pola. CONCLUSIONS: Pola PK was well characterized with no clinically meaningful DDIs with R/G-CHP. Findings are consistent with previous studies of pola + R/G, and support pola + R/G-CHP use in previously untreated diffuse large B-cell lymphoma.

Free prednisolone pharmacokinetics predicted from total concentrations in patients with inflammatory - immunonologic conditions.

Prednisone is an anti-inflammatory drug widely used in internal medicine and rheumatology, but dosing remains empirical. The active metabolite of prednisone is free prednisolone. The aim of this work was to build a population pharmacokinetic (PK) model that can predict free prednisolone concentrations in patients with inflammatory/immunologic conditions.A total of 107 patients from the department of internal medicine of Cochin hospital provided 343 observations. Blood samples drawn for biological analyses were used for drug determination. Total plasma prednisolone concentrations were measured by liquid chromatography-mass spectrometry, and the data were modelled using Monolix. The pharmacokinetics was ascribed a one-compartment open model with three transit compartments standing for the absorption and metabolism process. The model used predicts free concentrations that served to derive total concentrations given published binding constants. Only size parameters influenced the pharmacokinetics. Free prednisolone CLU /F and VU /F, scaled allometrically on lean body weight, were, respectively, 26.7 L/h and 94.3 L for 50 kg LBW. CLU /F interindividual variability was 0.20. The additive and proportional residual variabilities were, respectively, 4.3 µg/L and 0.20. The results point out some dosing issues, that is the possibility of under- or over-dosage in thin or overweight patients respectively.

Tear Fluid Pharmacokinetics Following Oral Prednisone Administration in Dogs With and Without Conjunctivitis.

Purpose: To describe the pharmacokinetics (PK) of prednisone and prednisolone in tear fluid of dogs receiving oral prednisone at anti-inflammatory to immunosuppressive doses and to assess the impact of induced conjunctivitis on lacrimal drug levels. Methods: Six healthy Beagle dogs were administered 4 courses of prednisone at 0.5, 1.0, 2.0, and 4.0 mg/kg given orally once a day for 5 days. At steady state, topical histamine was applied to induce mild (1 mg/mL) or severe (375 mg/mL) conjunctivitis in 1 eye of each dog and tear samples were collected from both eyes at selected times. Prednisone and prednisolone were quantified in tears by liquid chromatography-mass spectrometry. Results: Lacrimal prednisone and prednisolone concentrations ranged from 2 to 523 ng/mL and 5 to 191 ng/mL, respectively. Drug concentrations were overall greater in dogs receiving higher doses of prednisone, but were not correlated with tear flow rate. Eyes with conjunctivitis often had larger amounts of prednisone and prednisolone in tear fluid compared to control eyes (up to +64%), but differences were not statistically significant. Significantly greater, but clinically insignificant, levels of prednisolone were found in eyes with severe versus mild conjunctivitis for oral prednisone doses ≥1.0 mg/kg. Conclusions: Disruption of the blood-tear barrier with conjunctivitis did not significantly affect drug levels in tears. Based on drug PK in tears, oral prednisone is likely safe for the management of reflex uveitis and ocular surface diseases. However, further prospective trials using systemic corticotherapy in diseased animals are warranted to confirm findings from this preclinical study.

Cyclophosphamide dose adjustment based on body weight and albuminemia in elderly patients treated with R-mini-CHOP.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in elderly patients, and R-CHOP chemotherapy is the standard treatment protocol for DLBCL. Elderly patients (often defined as 75 years of age) are treated with anticancer drugs with precaution; however, the pharmacokinetics and pharmacodynamics (PK and PD) of these agents have not been thoroughly investigated in this population. In this study, we investigated the PK of cyclophosphamide (CP) and doxorubicin (DOXO) in elderly patients in order to verify if there is an influence of age on the PK of these anticancer drugs. MATERIALS AND METHODS: This is a prospective multi-center clinical trial investigating the PK of CP and DOXO in elderly and very elderly patients with DLBCL treated by R-mini-CHOP regimen. Dose levels were 25 mg/m2, 0.7-1.4 mg/m2, 750 mg/m2, and 375 mg/m2 for DOXO, Vincristine (VCR), CP, and Rituximab, respectively. For PK analysis, 7 time point samples were collected over 48 h post-administration on cycle 3. CP and VCR plasma concentrations were measured using UPLC-MS/MS validated method. DOX plasma concentrations were measured using UPLC coupled with fluorescence detection-validated method. PK-POP modeling has been performed with a non-linear mixed-effect model program (Monolix). RESULTS: 31 patients (15 males and 16 females), 75 to 96 years old, were treated with R-miniCHOP protocol. Among them, 19 patients were treated with VCR. A one-compartment (1cpt) open model with linear elimination adequately described CP concentration-time courses. The population PK parameters for CP were: CL = 3.58 L/h, Vmale = 32.2 L, and Vfemale = 28.7 L. Body weight (BW), albuminemia, and gender demonstrated a significant impact on CP PK. A 2-compartment (2cpt) open model with linear elimination best described DOXO concentration-time courses. The population PK parameters for DOXO obtained for the structural model were: CL = 51.1 L/h, Q = 49.6 L/h, V1 = 29.4 L, V2 = 1,130 L (clearances: CL, Q, volumes of distribution: V1, V2). The main covariate effects on DOXO PK were related to gender, BW, and VCR administration. VCR increases DOXO V1 from 29.4 L to 57.5 L (p = 0.02). No hematologic and cardiac grade 3 or 4 toxicity were recorded. CONCLUSIONS: Usually, in the absence of specific data, the majority of the physicians empirically reduce anticancer drug dose in the elderly patients (Tourani in J Geriatr Oncol 3(1): 41-48, 2012), or even does not treat these very-old patients. A better knowledge of the pharmacokinetics in very-old patients should allow a better dose adjustment based on the most significant physiological factors that modify the pharmacokinetic parameters. In this study, no serious toxicity was observed in these very elderly patients (84.1 years). This indicates that dose adjustment of chemotherapies should not only be based on age and creatinine clearance, but also, based upon appropriate physiological and biological data. Our findings indicate that, CP dose adjustment should be done according to serum albumin levels and patients BW and gender.

Estudio comparativo de perfiles de disolución de tabletas de prednisona 20 mg comercializados en Perú / Comparative study of dissolution profiles of prednisone 20 mg tablets marketed in Peru

El estudio tuvo como finalidad comparar los perfiles de disolución de tabletas de prednisona 20 mg comercializados en Perú. Se realizó un estudio cuantitativo comparativo con diseño no experimental, que incluyó doce tabletas para cada formulación a evaluar (referente y multifuente), bajo condiciones similares de trabajo, en tres medios de disolución: buffer ácido clorhídrico pH 1,2; buffer acetato pH 4,5 y buffer fosfato pH 6,8. Los porcentajes temporales disueltos de prednisona fueron evaluados mediante el orden cinético cero, uno, Higuchi, raíz cúbica y Weibull para el modelo dependiente; mientras que el factor de similitud (f2), tiempo medio de disolución y eficiencia de disolución fueron utilizados para el modelo independiente. En el modelo dependiente, la liberación de prednisona; se ajustó a la cinética de función de Weibull; evaluada mediante el criterio de información de Akaike. En el modelo independiente, los valores de f2 en todos los medios de disolución cumplieron con el rango 50 - 100 establecida por la Food and Drug Adminstration, para indicar similitud in vitro entre los perfiles de disolución. Asimismo, se evidenció que no existe diferencia estadísticamente significativa entre las formulaciones, respecto al tiempo medio de disolución y la eficiencia de disolución. Las tabletas de prednisona 20 mg referente y multifuente comercializados en Perú son similares, con base en pruebas de perfiles de disolución in vitro(AU)

The purpose of the study was to compare the dissolution profiles of prednisone 20 mg tablets marketed in Peru. A comparative quantitative study with a non-experimental design was carried out, which included twelve tablets for each formulation to be evaluated (referent and multi-source), under similar work conditions in three dissolution media: hydrochloric acid buffer pH 1.2, acetate buffer pH 4.5 and phosphate buffer pH 6.8. The dissolved temporal percentages of prednisone were evaluated by zero kinetic order and first kinetic order, Higuchi, cubic root and Weibull models for the dependent model; while the similarity factor (f2), mean dissolution time and dissolution efficiency were used for the independent model. In the dependent model, the release of prednisone was adjusted to the Weibull function kinetics, evaluated using the Akaike information criterion. In the independent model, the values of f2 in all the dissolution media fulfilled the range 50 - 100 established by the Food and Drug Administration, to indicate in vitro similarity between the dissolution profiles. Likewise, it was evidenced that there is no statistically significant difference between the formulations with respect to the mean dissolution time and the dissolution efficiency. The reference and multi-source prednisone 20 mg tablets marketed in Peru are similar based on in vitro dissolution profiles tests(AU)

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.

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.

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.

Prednisone Pharmacokinetics During Pregnancy and Lactation.

To evaluate the steady-state pharmacokinetics of prednisone and its metabolite prednisolone in pregnant and lactating female subjects, 19 subjects received prednisone (4-40 mg/day orally) in early (n = 3), mid (n = 9), and late (n = 13) pregnancy as well as postpartum with (n = 2) and without (n = 5) lactation. Serial blood and urine samples were collected over 1 dosing interval. Prednisone and its metabolite, prednisolone, steady-state noncompartmental pharmacokinetic parameters were estimated. During pregnancy, prednisone apparent oral clearance increased with dose (35.1 ± 11.4 L/h with 5 mg, 52.6 ± 5.2 L/h with 10 mg, and 64.3 ± 6.9 L/h with 20 mg, P = .001). Similarly, unbound prednisone apparent oral clearance increased with dose. In addition, prednisolone renal clearance increased with dose (0.3 ± 0.3 L/h with 5 mg, 0.5 ± 0.4 L/h with 10 mg, and 1.3 ± 1.1 L/h with 20 mg, P = .002). Higher prednisone (r = 0.57, P ≤ .05) and prednisolone (r = 0.75, P ≤ .05) concentrations led to a higher percentage of unbound drug. Breast-milk/plasma area under the concentration-time curve ratios were 0.5-0.6 for prednisone and 0.02-0.03 for prednisolone. Relative infant doses were 0.35% to 0.53% and 0.09% to 0.18%, for prednisone and prednisolone, respectively. Prednisone and prednisolone exhibit dose- and concentration-dependent pharmacokinetics during pregnancy, and infant exposure to these agents via breast milk is minimal.

Effect of Treating Acute Optic Neuritis With Bioequivalent Oral vs Intravenous Corticosteroids: A Randomized Clinical Trial.

Importance: Intravenous (IV) administration of corticosteroids is the standard of care in the treatment of acute optic neuritis. However, it is uncertain whether a bioequivalent dose of corticosteroid administered orally, which may be more cost-efficient and convenient for patients, is as effective as IV administration in the treatment of acute optic neuritis. Objective: To determine whether recovery of vision following treatment of acute optic neuritis with a high-dose IV corticosteroid is superior to that with a bioequivalent dose of an oral corticosteroid. Design, Setting, and Participants: This single-blind (participants unblinded) randomized clinical trial with 6-month follow-up was conducted at a single tertiary care center in London, Ontario, Canada. Participants were enrolled from March 2012 to May 2015, with the last participant's final visit occurring November 2015. Patients 18 to 64 years of age presenting within 14 days of acute optic neuritis onset, without any recovery at time of randomization and without history of optic neuritis in the same eye, were screened. Inclusion criteria included best-corrected visual acuity (BCVA) of 20/40 or worse and corticosteroids deemed required by treating physician. In total, 89 participants were screened; 64 were eligible, but 9 declined to participate. Thus, 55 participants were enrolled and randomized. Primary analysis was unadjusted and according to the intention-to-treat principle. Interventions: Participants were randomized 1:1 to the IV methylprednisolone sodium succinate (1000-mg) or oral prednisone (1250-mg) group. Main Outcomes and Measures: Primary outcome was recovery of the latency of the P100 component of the visual evoked potential at 6 months. Secondary outcomes were the P100 latency at 1 month and BCVA as assessed with Early Treatment Diabetic Retinopathy Study letter scores on the alphabet chart and scores on low-contrast letters at 1 and 6 months. Results: Of 55 randomized participants, the final analyzed cohort comprised 23 participants in the IV and 22 in the oral treatment groups. The mean (SD) age of the cohort was 34.6 (9.5) years, and there were 28 women (62.2%). At 6 months' recovery, P100 latency in the IV group improved by 62.9 milliseconds (from a mean [SD] of 181.9 [53.6] to 119.0 [16.5] milliseconds), and the oral group improved by 66.7 milliseconds (from a mean [SD] of 200.5 [67.2] to 133.8 [31.5] milliseconds), with no significant difference between groups (P = .07). Similarly, no significant group difference was found in the mean P100 latency recovery at 1 month. For BCVA, recovery between the groups did not reach statistical significance at 1 month or 6 months. In addition, improvements in low-contrast (1.25% and 2.5%) BCVA were not significantly different between treatment groups at 1 or 6 months' recovery. Conclusions and Relevance: This study finds that bioequivalent doses of oral corticosteroids may be used as an alternative to IV corticosteroids to treat acute optic neuritis. Trial Registration: clinicaltrials.gov Identifier: NCT01524250.

Pharmacokinetic Interactions Between Elbasvir/Grazoprevir and Immunosuppressant Drugs in Healthy Volunteers.

Elbasvir (EBR)/grazoprevir (GZR) may be coadministered with immunosuppressant drugs in posttransplant people who are infected with hepatitis C virus. The aim of the present study was to assess the safety and pharmacokinetic interactions between EBR and GZR and single doses of cyclosporine, tacrolimus, mycophenolate mofetil (MMF), and prednisone. This was a 4-part, open-label study in 58 healthy volunteers. Participants received single doses of cyclosporine 400 mg, tacrolimus 2 mg, MMF 1 g, or prednisone 40 mg alone or in the presence of once-daily EBR 50 mg/GZR 200 mg. Multiple oral doses of EBR + GZR had no significant effect on cyclosporine. However, in the presence of cyclosporine, the 24-hour area under the concentration-time curve of GZR was increased by approximately 15-fold (geometric mean ratio [90%CI] 15.21 [12.83; 18.04]); the concentration of EBR was increased approximately 2-fold in the presence of cyclosporine. Coadministration of EBR/GZR and tacrolimus did not affect the pharmacokinetics of EBR or GZR, but resulted in an increase in tacrolimus AUC (geometric mean ratio [90%CI] 1.43 [1.24; 1.64]). There were no clinically relevant interactions between EBR/GZR and either MMF or prednisone. Data from the present study indicate that EBR/GZR may be coadministered in people receiving tacrolimus, MMF, and prednisolone. EBR/GZR is contraindicated in people receiving cyclosporine because the significantly higher concentrations of GZR may increase the risk of transaminase elevations.

Population Pharmacokinetics of Fosdagrocorat (PF-04171327), a Dissociated Glucocorticoid Receptor Agonist, in Patients With Rheumatoid Arthritis.

Dissociated agonists of the glucocorticoid receptor (DAGRs) show similar antiinflammatory effects but improved tolerability compared with standard glucocorticoid receptor (GR) agonists. The prodrug fosdagrocorat (PF-04171327), with active DAGR metabolite PF-00251802 (Metabolite-1), is postulated to show superior efficacy over placebo and prednisone in patients with moderate to severe rheumatoid arthritis (RA). We investigated the population pharmacokinetics of active Metabolite-1 and its active metabolite PF-04015475 (Metabolite-2) in patients with moderate to severe RA enrolled in a 12-week, phase II, randomized, double-blind study (NCT01393639). A simultaneous fit of a two-compartment model for Metabolite-1 and a one-compartment model for Metabolite-2 provided an adequate fit to the data. Significant covariates included weight, with an additional female effect on clearance of Metabolite-1 (∼26%) and Metabolite-2 (∼33%) compared with males. Age influenced clearance of Metabolite-1. In combination, age, weight, and sex predicted >twofold differences in area under the concentration-time curve of Metabolite-1 at the extremes.

Randomized phase 2 therapeutic equivalence study of abiraterone acetate fine particle formulation vs. originator abiraterone acetate in patients with metastatic castration-resistant prostate cancer: The STAAR study.

BACKGROUND: This multicenter, randomized, open-label, active-controlled study evaluated therapeutic equivalence, steady-state pharmacokinetics, and safety of a novel abiraterone acetate fine particle formulation (AAFP) 500mg plus methylprednisolone vs. the originator AA (OAA) 1000mg plus prednisone in men with metastatic castrate-resistant prostate cancer (mCRPC). The primary endpoint was a comparison of average of serum testosterone levels on treatment days 9 and 10 between groups. METHODS: Men with progressive mCRPC, receiving gonadotropin-releasing hormone agonist or antagonist therapy, and with a serum testosterone level of <50ng/dl were randomized 1:1 to either AAFP 500mg daily plus 4mg methylprednisolone orally twice daily (BID), or OAA 1000mg daily plus 5mg prednisone BID for 84 days. Serum testosterone, serum prostate-specific antigen (PSA), steady-state (trough) abiraterone pharmacokinetics, and safety were evaluated. RESULTS: Fifty-three patients were enrolled (n = 24, AAFP; n = 29, OAA). Mean age was 75.1 years and 54.7% had Gleason>7. Over 90% of patients in each group achieved absolute testosterone levels of ≤1ng/dl during the study. The averaged absolute testosterone levels ≤0.1ng/dl were achieved in 25% of AAFP-treated patients and 17% of OAA-treated patients. A PSA-50 response was observed in>65% of patients in both groups on days 28, 56, and 84 (P = NS, all timepoints). Days 9 and 10 averaged rounded-up least squares (LS) mean (SE) serum testosterone levels were comparable (1.05ng/dl [0.04], AAFP; 1.02ng/dl [0.03], OAA; P = 0.4703 for LS mean difference). The geometric mean ratio between groups was 1.021 (90% CI: 0.965-1.081); the 90% CI fell within 80.0% to 125.0% equivalence limits. The LS mean differences in abiraterone trough plasma concentrations were not statistically significant at any visit. Adverse event frequency was comparable between arms (75.0%, AAFP; 82.8%, OAA). Musculoskeletal events were more common among OAA-treated patients (37.9% vs. 12.5%). CONCLUSION: Therapeutic equivalence between AAFP 500mg daily and OAA 1000mg daily based on serum testosterone levels was confirmed in mCRPC patients. Both agents led to similar PSA-50 response rates. Abiraterone trough levels were similar between treatments. No new safety concerns were observed.