Relative bioavailability of cyclosporin from conventional and microemulsion formulations in heart-lung transplant candidates with cystic fibrosis

Patients with cystic fibrosis absorb cyclosporin poorly and erratically. We have compared the relative bioavailability of cyclosporin from conventional and microemulsion formulations in 5 adult heart-lung transplant candidates with cystic fibrosis. Relative bioavailability was compared at two dose levels (200 mg and 800 mg). A randomized 4-period cross-over study was performed with at least a 7 days washout period between each single dose pharmacokinetic study. Blood cyclosporin concentrations were measured by a selective monoclonal antibody-based radioimmunoassay. The bioavailability of cyclosporin from the microemulsion formulation was 1.84 (95% C.I. 1.05 to 3.22; P–0.04) and 2.09 (95% C.I. 0.95 to 4.61; P–0.06) times higher compared with the conventional formulation at 200 mg and 800 mg respectively. C_max following the microemulsion formulation was 3.38 (C.I. 1.14 to 10.59; P–0.04) and 2.77 (C.I. 1.48 to 5.19; P–0.01) times higher compared with the conventional formulation at 200 mg and 800 mg respectively. The higher C_max following the microemulsion formulation was accompanied by shorter t_max. An enhancement of cyclosporin absorption with the microemulsion formulation was demonstrated in each patient for at least one dose level. We conclude that rate and extent of cyclosporin absorption from the microemulsion formulation is greater compared with the conventional formulation in patients with cystic fibrosis. The potential therapeutic and economic benefits of the micro-emulsion formulation should be evaluated in cystic fibrosis patients following heart-lung transplantation.     

Population pharmacokinetics of mycophenolic acid and its glucuronide metabolite in lung transplant recipients with and without cystic fibrosis

1.?Cystic fibrosis (CF) is a disease affecting multiple organs that may reduce the systemic exposure of some drugs. The objective of this work was to characterize and compare the population pharmacokinetics (PK) of the immunosuppressant mycophenolic acid (MPA), and its glucuronide metabolite (MPAG) in adult lung transplant recipients with and without CF (NCF) following repeated oral administration of the prodrug mycophenolate mofetil (MMF).

2.?A population PK model was developed, with simultaneous modeling of MPA and MPAG, using nonlinear mixed effects modeling. MPA and MPAG serum concentration-time data were adequately described by a compartmental model including enterohepatic recirculation (EHR). Both MPA and MPAG apparent clearance values were significantly elevated (>65%) in patients with CF (24.1 and 1.95?L/h, respectively) compared to the values in the NCF patients (14.5 and 1.12?L/h, respectively), suggesting a notable influence of CF on MPA absorption and disposition.

3.?The population PK model developed from our study successfully characterized the absorption, distribution, elimination and EHR of MPA and the metabolite MPAG in lung transplant recipients with or without CF. This model may help to further understand the impact of CF to the overall clinical effects of MPA therapy including immunosuppression and gastrointestinal side effects.     

Altered pharmacokinetics of cyclosporin in heart-lung transplant recipients with cystic fibrosis

The cyclosporin dose versus blood concentration relationship for 11 heart-lung transplant recipients with cystic fibrosis was studied retrospectively. Eleven patients, closely matched for age and gender, who received heart-lung transplantation for other diseases were selected as controls. Cystic fibrosis patients received 16.7 (SD 7.2) mg/kg/day of oral cyclosporin compared with 8.2 (SD 1.9) mg/kg/day given to the control patients (p less than 0.01). Nine of the cystic fibrosis patients received higher mean daily doses of cyclosporin. Mean blood cyclosporin concentrations were, however, not significantly different (p = 0.58), and there were no apparent differences in clinical outcome in terms of rejection, infection, and nephrotoxicity in the two groups. The apparent oral clearance of cyclosporin was significantly higher (p less than 0.01) in cystic fibrosis patients. Cyclosporin dosage individualization with the aid of cyclosporin blood concentration measurements is critically important in this subpopulation of heart-lung transplant recipients.     

Clinical pharmacokinetics of antimicrobial drugs in cystic fibrosis.

The disposition of many drugs in cystic fibrosis is abnormal compared with healthy individuals. In general, changes include an increased volume of distribution expressed in liters per kg bodyweight for highly hydrophilic drugs such as aminoglycosides, and, to a lesser extent, for penicillins and cephalosporins, together with an increased total body clearance. The main reason for the increased volume of distribution is the increased amount of lean tissue per kg bodyweight, since patients with CF are generally undernourished and have a paucity of adipose tissue. The reason for the increased renal clearance is less clear. Increased glomerular filtration and tubular secretion have been observed. Protein binding generally is unaltered in CF. The fluorquinolones and vancomycin show no altered pharmacokinetics in CF although gastro-intestinal absorption may be delayed for fluorquinolones. Sulphamethoxazole shows increased clearance due to an increased acetylation and, in the case of trimethoprim, renal clearance is increased compared with healthy individuals. As a consequence, drugs that show increased clearance, will lead to reduced serum concentrations and smaller AUCs and therefore CF patients require larger doses per kg bodyweight.     

Bayesian forecasting of oral cyclosporin pharmacokinetics in stable lung transplant recipients with and without cystic fibrosis

The aims of the current study were (1) to study Neoral pharmacokinetics (PK) in stable lung recipients with or without cystic fibrosis (CF), (2) to compare Neoral PK between these two groups, and (3) to design Bayesian estimators for PK forecasting and dose adjustment in these patients using a limited number of blood samples. The individual PK of 19 adult lung transplant recipients, 9 subjects with CF and 10 subjects without CF, were retrospectively studied. Three profiles obtained within 5 days were available for each patient. A PK model combining a gamma distribution to describe the absorption profile and a two-compartment model were applied. Different exposure indices were estimated using nonlinear regression and Bayesian estimation. The PK model developed reliably described the individual PK of Neoral in lung transplant patients with and without CF, and the values of the first and second half-lives were different in these two populations (lambda(1) = 4.14 +/- 3.01 vs. 2.16 +/- 1.75 h(-1); P < 0.01; lambda(2) = 0.36 +/- 0.11 vs. 0.49 +/- 0.12 h(-1); P < 0.01), while the mean absorption time and standard deviation of absorption time tended to be less in patients with cystic fibrosis (P < 0.1). Also, the patients with CF required higher doses than those without CF to achieve similar drug exposure. Consequently, population modeling was performed in CF and non-CF patients separately. Bayesian estimation allowed accurate prediction of AUC(0-12), AUC(0-4), C(max), and T(max) using three blood samples collected at T0h, T1h, and T3h in both groups. This study demonstrated the applicability and good performance of the PK model previously developed for oral cyclosporin and of the MAP Bayesian estimation of cyclosporin systemic exposure in CF and non-CF patients. Moreover, it is the first to propose a monitoring tool specifically designed for cyclosporin monitoring in patients with CF.     

Poor tolerability of cystic fibrosis transmembrane conductance regulator modulator therapy in lung transplant recipients

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is a highly effective therapy for patients with cystic fibrosis (CF) with potential benefits in lung transplant recipients (LTRs) for extrapulmonary CF manifestations; however, tolerability and efficacy in this population are largely unknown. We report our experience with ELX/TEZ/IVA in LTRs for extrapulmonary complications of CF including tolerability, drug–drug interactions, and therapeutic benefit. All LTRs at a single center initiated on ELX/TEZ/IVA were reviewed. Adverse events and patient-reported outcomes attributed to ELX/TEZ/IVA were documented. Pulmonary function, tacrolimus requirements in mg/kg/dl, body mass index (BMI), and reason for initiation were assessed at the initiation of ELX/TEZ/IVA, and at 12 months post-initiation or at the time of discontinuation for those in whom therapy was discontinued. Thirteen LTRs were initiated on ELX/TEZ/IVA at a mean of 115 ± 92 months post-transplant. All were initiated on ELX/TEZ/IVA for sinus or sinus and gastrointestinal CF manifestations. Five (38.4%) patients discontinued therapy due to declining pulmonary function (2/5, 40%), mood disturbances (2/5, 40%), or lack of benefit (1/5, 20%). Of the eight patients who remain on ELX/TEZ/IVA, four reported adverse effects and three LTRs temporarily held therapy. Six (46.2%) LTRs reported improvement in sinus symptoms, while four (30.7%) reported improved gastrointestinal symptoms. Weight declined in the cohort overall. Tacrolimus dose requirements decreased following initiation of ELX/TEZ/IVA therapy, with a 50% decline in dose requirements observed. In our experience, ELX/TEZ/IVA in LTRs is poorly tolerated with modest perceived extrapulmonary benefit and a significant effect on tacrolimus dose requirements. More data are needed to determine the benefits of ELX/TEZ/IVA therapy in LTRs.     

Pharmacological management of cystic fibrosis related diabetes

Introduction: There are limited data from randomized clinical trials to guide optimal options for pharmacological treatment of cystic fibrosis related diabetes (CFRD). Current guidelines recommend insulin as the only treatment option for CFRD.

Areas covered: Current guidelines for screening, diagnosis and pharmacological agents for treatment of impaired glucose tolerance and CFRD in patients with cystic fibrosis are reviewed. Insights from clinical studies examining the role of insulin therapy in CFRD are presented.

Expert commentary: CFRD is the most common extra pulmonary complication of cystic fibrosis, and is primarily related to insulin insufficiency. Insulin is the treatment of choice for CFRD. Insulin treatment is associated with improvement in glycemic control, nutritional status and lung function. Current data does not support use of oral hypoglycemic agents for treatment of CFRD.     

A comparison of the pharmacokinetics of tacrolimus and microemulsified cyclosporin in paediatric renal transplant recipients

Objective Our objective was to identify common factors that determine the dose of tacrolimus and microemulsified cyclosporin in paediatric renal transplant recipients.Methods The concentration profiles of tacrolimus and cyclosporin in blood were determined in 68 children who had received a renal transplant. To avoid disruption of therapy, measurements were made at 2-h intervals over an 8-h period during normal dosing regimens. Direct comparisons of the two drugs were made in 14 of the subjects who were switched from cyclosporin to tacrolimus.Results The ratio of peak to trough levels for tacrolimus was approximately twofold compared with over threefold for cyclosporin. Area under the curve (AUC) for tacrolimus remained relatively constant in each 2-h period of the dosage interval compared with the AUC for cyclosporin, which varied by over twofold in the same time period. In the 14 subjects who received both drugs, there was a poor correlation between C₂/C₀, C₂, t_1/2 and AUC for tacrolimus and cyclosporin in the same individual. In a multivariate analysis, there were no significant associations for tacrolimus concentrations, AUC or C₂/C₀ with age, gender, calcium-channel blocker, quinolone or statin. For cyclosporin, there was some association for AUC with gender and quinolone use and a weak association with calcium-channel blocker or statin use.Conclusions Tacrolimus and microemulsified cyclosporin display a wide intra- and inter-individual variation in pharmacokinetic properties in young subjects. In the case of absorption represented by the peak-trough ratios, the values for tacrolimus are significantly less than those obtained with cyclosporin. The pharmacokinetic parameters obtained for one of these agents is not predictive for the behaviour of the other in young renal transplant recipients.     

An update on new and emerging therapies for cystic fibrosis

Introduction: Cystic fibrosis (CF) is a genetic disorder that results in a multi-organ disease with progressive respiratory decline that ultimately leads to premature death. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which codes for the CFTR anion channel. Established CF treatments target downstream manifestations of the primary genetic defect, including pulmonary and nutritional interventions.

Areas covered: CFTR modulators are novel therapies that improve the function of CFTR, and have been approved in the past five years to mitigate the effects of several CF-disease causing mutations. This review summarizes currently approved CFTR modulators and discusses emerging modulator therapies in phase II and III clinical trials described on clinical trials.gov as of April, 2017. Results of relevant trials reported in peer-reviewed journals in Pubmed, scientific conference abstracts and sponsor press releases available as of November, 2017 are included.

Expert opinion: The current scope of CF therapeutic development is robust and CFTR modulators have demonstrated significant benefit to patients with specific CFTR mutations. We anticipate that in the future healthcare providers will be faced with a different treatment paradigm, initiating CFTR-directed therapies well before the onset of progressive lung disease.     

Challenges with current inhaled treatments for chronic Pseudomonas aeruginosa infection in patients with cystic fibrosis

Abstract

Background:

Pseudomonas aeruginosa (Pa) is the predominant pathogen infecting the airways of patients with cystic fibrosis (CF). Initial colonization is usually transient and associated with non-mucoid strains, which can be eradicated if identified early. This strategy can prevent, or at least delay, chronic Pa infection, which eventually develops in the majority of patients by their late teens or early adulthood. This article discusses the management and latest treatment developments of Pa lung infection in patients with CF, with a focus on nebulized antibiotic therapy.     

Population pharmacokinetics of melphalan in paediatric blood or marrow transplant recipients

AIM: To develop a population pharmacokinetic model for melphalan in children with malignant diseases and to evaluate limited sampling strategies for melphalan. METHODS: Melphalan concentration data following a single intravenous dose were collected from 59 children with malignant diseases aged between 0.3 and 18 years. The data were split into two sets: the model development dataset (39 children, 571 concentration observations) and the model validation dataset (20 children, 277 concentration observations). Population pharmacokinetic modelling was performed with the NONMEM software. Stepwise multiple linear regression was used to develop a limited sampling model for melphalan. RESULTS: A two-compartment model was fitted to the concentration-vs.-time data. The following covariate population pharmacokinetic models were obtained: (i) Clearance (l h(-1)) = 0.34.WT - 3.17.CPT + 0.0377.GFR, where WT = weight (kg), CPT = prior carboplatin therapy (0 = no, 1 = yes), and GFR = glomerular filtration rate (ml min(-1) 1.73 m(-2)); (ii) Volume of distribution (l) = 1.12 + 0.178.WT. Interpatient variability (coefficient of variation) was 27.3% for clearance and 33.8% for volume of distribution. There was insignificant bias and imprecision between observed and model-predicted melphalan concentrations in the validation dataset. A three-sample limited sampling model was developed which adequately predicted the area under the concentration-time curve (AUC) in the development and validation datasets. CONCLUSIONS: A population pharmacokinetic model for melphalan has been developed and validated and may now be used in conjunction with pharmacodynamic data to develop safe and effective dosing guidelines in children with malignant diseases.     

Plasma esterases in cystic fibrosis: the impact of a respiratory exacerbation and its treatment

Objectives: To determine the effect of an exacerbation of respiratory symptoms in cystic fibrosis (CF) on the activities of plasma benzoylcholinesterase and butyrylcholinesterase. Methods: Twenty-nine patients with CF in a respiratory exacerbation and 27 healthy volunteers matched for age and sex were recruited. Blood was obtained from the patients when commencing antibiotic treatment and 14 days later on completion of treatment. One blood sample was taken from the healthy volunteers. The activities of benzoylcholinesterase and butyrylcholinesterase were determined by spectrophotometric assay. The circulating inflammatory markers, C-reactive protein and neutrophil elastase-α₁antiproteinase complex were also measured. Results: Benzoylcholinesterase activity was significantly (P = 0.001) lower in patients at the start of a respiratory exacerbation, compared with healthy controls [mean (SD): 917 (274) versus 1191(298) nmol · ml⁻¹ · min⁻¹]. Benzoylcholinesterase activity increased significantly in patients to 1013 (237) nmol · ml⁻¹ · min⁻¹, following a course of antibiotic treatment (P = 0.006). Butyrylcholinesterase activity was also lower (P = 0.001) in patients at the start of a respiratory exacerbation, compared with healthy controls [5.54 (1.64) versus 7.01 (1.79) μmol · ml⁻¹ · min⁻¹], and increased significantly in the patients to 6.31 (1.58) μmol · ml⁻¹ · min⁻¹ following treatment (P = 0.006). Conclusion: We demonstrated significant suppression of plasma esterase activities during an exacerbation of respiratory symptoms in CF, which was only partially reversed after antibiotic treatment. Further studies are needed to examine other pathways of drug metabolism in this group of chronically infected patients. Received: 8 June 1998 / Accepted in revised form: 18 September 1998     

Reduced exhaled NO is related to impaired nasal potential difference in patients with cystic fibrosis

Nitric oxide (NO) plays a central role in many airway physiological functions, and its production appears to be related with progression of lung disease in patients with cystic fibrosis (CF). However, underlying mechanisms which specifically link NO and CF-related lung disease remain unclear. Following in vitro and animal studies suggesting a role for NO in ion transport in various epithelia, this work investigates the relationship between transepithelial baseline potential difference (BPD), an index of airway ion transport, and exhaled NO in the airways of adult patients with CF. Association with other phenotypic traits, lung function tests and CFTR genotype was also assessed. Using simple linear regression, F(E)NO and transepithelial BPD values were significantly inversely correlated (p<0.001, r=-0.53). Polynomial analysis evidenced an asymptotic relationship between F(E)NO and BPD values, yielding a plateau for absolute BPD values above 50 mV. This relation was not altered by adjustment for clinical and genetic characteristics of the patients. The relationship between exhaled NO and transepithelial BPD suggests that low NO concentrations likely worsens airway ion transport impairment resulting from CFTR defect. These results fit with experimental studies that suggest the inhibitory effect of NO on sodium absorption, which is the main determinant of airway basal transepithelial conductance.     

Antimicrobial susceptibility of non-fermenting Gram-negative pathogens isolated from cystic fibrosis patients

Non-fermenting Gram-negative bacteria (NFGNB) are increasingly cultured in respiratory samples from cystic fibrosis (CF) patients. This study determined the antimicrobial susceptibility of clinical CF respiratory isolates from distinct geographical regions. A total of 286 isolates (106 Stenotrophomonas maltophilia, 100 Burkholderia spp., 59 Achromobacter spp., 12 Pandoraea spp., 9 Ralstonia spp.) from the Netherlands, Northern Ireland, Spain, USA and Australia were tested. MIC_50/90 values and susceptibility categorisation were determined. Trimethoprim/sulfamethoxazole (SXT) was the most active compound for all micro-organisms (MIC₅₀, 0.12–4 mg/L; MIC₉₀, 1–16 mg/L). For S. maltophilia, 47% and 62% of isolates were susceptible to SXT according to CLSI and EUCAST breakpoints, respectively. Ceftazidime presented lower susceptibility (35%; MIC₅₀, 32 mg/L; MIC₉₀, 256 mg/L). MIC₉₀ values for tobramycin and colistin were >128 mg/L and >16 mg/L, respectively. Regarding Burkholderia, 72%, 56% and 44% were susceptible to SXT, ceftazidime and meropenem, respectively. For both ceftazidime and meropenem, MIC₅₀ and MIC₉₀ values were within the intermediate or resistant category. The most active antibiotics for Achromobacter spp. were SXT (MIC₅₀, 0.5 mg/L; MIC₉₀, 8 mg/L) and imipenem (MIC₅₀, 2 mg/L; MIC₉₀, 8 mg/L). SXT, imipenem and ciprofloxacin were active against 12 Pandoraea spp. (MIC₅₀, 0.12–4 mg/L; MIC₉₀, 1–8 mg/L). Ciprofloxacin (MIC₅₀, 4 mg/L) and SXT (MIC₅₀, 1 mg/L) were the only active antibiotics for Ralstonia spp. There were no statistically significant differences in susceptibility rates between countries. NFGNB other than Pseudomonas aeruginosa are potential pathogens in CF. SXT was demonstrated to be the most active compound against these isolates.     

Population pharmacokinetics of valganciclovir prophylaxis in paediatric and adult solid organ transplant recipients

Aim

Our aims were to quantify ganciclovir pharmacokinetics in paediatric and adult kidney, liver and lung transplant patients taking a range of valganciclovir doses to prevent herpes virus infections, including a 450 mg regimen, and to identify sources of pharmacokinetic variability.

Method

Plasma samples were collected at 2, 4, 8 and 12 weeks post-transplant and at 4, 6, 8 and 12 months post-transplant in subjects prescribed longer courses. Ganciclovir was measured by liquid chromatography/ultraviolet detection. Non-linear mixed effects modelling was used to analyze the concentration–time data and evaluate demographic and transplant-related covariates.

Results

A two compartment model with first order absorption best described the data. Given the range of body sizes, clearance and volume of distribution terms were scaled using standard weight-based allometric exponents. Creatinine clearance was included on apparent oral clearance. Final estimates in a standard 70 kg individual for apparent oral clearance, central volume of distribution, intercompartmental clearance and peripheral volume of distribution were 14.5 l h⁻¹, 87.5 l, 4.80 l h⁻¹ and 42.6 l, respectively. The median terminal half-life for kidney, liver and lung transplant recipients was 9.4, 9.5 and 8.2 h, respectively. Median exposure (i.e. AUC(0,∞) in subjects taking valganciclovir 900 mg or 450 mg once daily was 57.4 and 34.3 μg ml⁻¹ h, respectively.

Conclusion

Allometric scaling allowed simultaneous analysis of data from children and adults. Ganciclovir pharmacokinetics were similar among kidney, liver and lung transplant recipients. Ganciclovir exposure after valganciclovir 450 mg once daily may be suboptimal in some individuals and requires evaluation along with virologic outcomes data.     

The safety of lumacaftor and ivacaftor for the treatment of cystic fibrosis

Introduction: Lumacaftor-ivacaftor is indicated for treatment of cystic fibrosis (CF) in patients homozygous for the Phe-508del cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. In clinical trials, treated patients showed improved pulmonary function, reduced pulmonary exacerbations, and other benefits. This article reviews safety of this therapy.

Areas covered: Safety findings in ivacaftor, lumacaftor and combined therapy trials, and reported subsequently through post-approval evaluation, were accessed by PubMed and Google searches using key words ‘VX-770’, ‘ivacaftor’, ‘VX-809’, and ‘lumacaftor’. Transaminitis was seen in ivacaftor and combination trials. Non-congenital cataracts were seen in pre-clinical animal studies and in children taking ivacaftor and combined therapy. Dyspnea occurs in some patients taking lumacaftor and combined therapy and usually resolves without stopping treatment. Lumacaftor is a strong inducer of CYP3A while ivacaftor is a CYP3A sensitive substrate. Combination therapy can decrease systemic exposure of medications that are substrates of CYP3A, decreasing therapeutic effect. Co-administration of lumacaftor-ivacaftor with sensitive CYP3A substrates or CYP3A substrates with narrow therapeutic index is not recommended.

Expert opinion: Lumacaftor-ivacaftor therapy may be associated with ocular and hepatic side effects. Specific recommendations for monitoring are available. Dyspnea occurs, especially during initiation of treatment. Potential drug interactions should be evaluated in patients taking combination therapy. The risk benefit ratio of lumacaftor-ivacaftor favors therapy.     

霉酚酸在肝移植受者的药代动力学与药效学相关性研究

目的研究肝移植受者早期口服霉酚酸(免疫抑制剂)药代动力学与药效学的相关性。方法20例肝移植受者口服霉酚酸酯前、后,用酶增强免疫法测定患者血浆霉酚酸浓度。服药前(0h)及服药后1,2h,用患者血清处理人急性淋巴细胞白血病T淋巴(CEM)细胞,检测CEM细胞的增殖情况。结果口服霉酚酸酯前,CEM细胞增殖率显著高于服药后1,2h(P<0.05);服药后1,2h霉酚酸浓度与相应的CEM细胞增殖率呈负相关(P<0.05)。结论肝移植受者口服霉酚酸酯后,血清对CEM细胞的增殖产生显著抑制作用,其作用和霉酚酸浓度呈显著负相关。