Pharmacokinetics of clarithromycin in bronchial epithelial lining fluid

Background and objective: BAL is an established technique for measuring antibiotic concentrations in the epithelial lining fluid (ELF) of the bronchiolar‐alveolar regions. However, the results may not reflect concentrations in bronchial regions. Bronchoscopic microsampling (BMS) is a technique for repeated sampling of bronchial ELF. The objective of the present study was to determine the time versus concentration profile of clarithromycin and its active metabolite, 14‐hydroxy‐clarithromycin, in bronchial ELF, as determined by BMS. Methods: BMS was performed at 1, 2, 3, 5 and 10 h after a single oral administration of 200 mg clarithromycin in five healthy volunteers. BAL was performed 3 h after administration to determine clarithromycin concentrations in alveolar ELF and alveolar macrophages (AM). Results: The maximum concentration (C_max) of clarithromycin was 0.36 ± 0.07 mg/L in serum and 1.44 ± 0.49 mg/L in bronchial ELF (P < 0.01). C_max for 14‐hydroxy‐clarithromycin was 0.34 ± 0.13 mg/L in serum and 0.68 ± 0.34 mg/L in bronchial ELF. The area under the concentration–time curve from 0 to 10 h (AUC_0‐10) for clarithromycin was 2.10 ± 0.49 mg·h/L for serum and 7.37 ± 2.07 mg·h/L for bronchial ELF (P < 0.01). The concentrations of clarithromycin in alveolar ELF and AM, 3 h after oral administration, were 4.84 ± 3.39 mg/L and 10.7 ± 8.7 mg/L, respectively. Conclusions: A single oral dose of clarithromycin produces a significantly higher C_max and AUC_0‐10 for clarithromycin in bronchial ELF than in serum, and higher concentrations in alveolar ELF and AM than in serum. BMS might be useful for measuring the pharmacokinetic profile of clarithromycin in bronchial ELF.     

Pharmacokinetics of new 625 mg nelfinavir formulation during pregnancy and postpartum

Objectives

Our objective was to evaluate the pharmacokinetics of nelfinavir (NFV) (625 mg tablets) 1250 mg twice daily during pregnancy and postpartum.

Methods

The participants were HIV‐1‐infected pregnant women enrolled in P1026s and receiving NFV (625 mg tablets) 1250 mg twice daily as part of routine clinical care. Intensive steady‐state 12‐h NFV pharmacokinetic profiles were performed during pregnancy and postpartum. The target NFV area under the plasma concentration–time curve (AUC_0–12) was ≥10th percentile NFV AUC_0–12 in non‐pregnant historical controls (18.5 μg h/mL).

Results

Of 27 patients receiving NFV, pharmacokinetic data were available for four (second trimester), 27 (third trimester) and 22 (postpartum) patients. The NFV maximum concentration (C_max), 12‐h post‐dose concentration (C₁₂) and AUC_0–12 were significantly lower during the third trimester compared to postpartum (P≤0.03). The metabolite hydroxyl‐tert‐butylamide (M8) AUC_0–12 and the M8/NFV AUC ratio were lower during the third trimester compared to postpartum (P<0.01). The NFV AUC_0–12 exceeded the AUC_0–12 target for 15/27 (56%) and 21/22 (95%) of third trimester and postpartum patients, respectively. The minimum concentration (C_min) was above the suggested minimum trough concentration (0.8 μg/mL) in 15% (third trimester) and 18% (postpartum). The plasma viral load was <400 HIV‐1 RNA copies/mL in 81% of patients at delivery.

Conclusions

These results suggest that higher doses of NFV should be considered during pregnancy.     

Dose–response relationship of insulin glulisine in subjects with type 1 diabetes

Aim: Little is known about the dose–response relationships of rapid‐acting insulin analogues in subjects with diabetes. This study compared the dose–exposure and dose–response relationships of insulin glulisine and regular human insulin (RHI) in subjects with type 1 diabetes. Methods: Eighteen male subjects with type 1 diabetes (mean glycosylated haemoglobin, HbA_1c, 7.7%; body mass index 24.5 kg/m²) received subcutaneous injections of insulin glulisine followed by RHI (both at doses of 0.075, 0.15 and 0.3 U/kg) in the same three‐way crossover, randomized order in a euglycaemic glucose‐clamp study. Results: Insulin glulisine and RHI showed dose‐proportional increases in exposure (INS‐AUC_total) and maximum serum concentration (INS‐C_max) in the dose ranges 0.075, 0.15 and 0.3 U/kg. At all doses, within 2 h after injection, about twice as much insulin glulisine was absorbed as RHI (INS‐AUC_0–2h: 3855, 6832 and 13237 vs. 2356, 3630 and 6231 μU.min/mL; p < 0.05) and INS‐C_max was reached in about half the time (INS‐T_max: 47, 57 and 72 vs. 82, 104 and 119 min; p < 0.05). Corresponding glucose disposition was twice as large with insulin glulisine as with RHI (GIR‐AUC_0–2h: 314, 491 and 536 vs. 127, 219 and 294 mg/kg; p < 0.05), but was similar in extent upon completion (GIR‐AUC_total: 499, 1090 and 1476 vs. 416, 1076 and 1555 mg/kg; not significant). With escalating doses, a steady increase in insulin exposure was noticed for both insulins across the entire dose range, whereas glucose disposition increased in a dose‐proportional manner only for the dose range 0.075–0.15 U/kg with insulin glulisine only. For both insulins, the end of euglycaemia occurred at insulin concentrations <10 μU/mL, with a subsequent rise in plasma glucose taking 80–90 min to reach ≥8.3 mmol/L (≥150 mg/dL) and a difference in time of ～120 min between the insulins at any dose. Conclusions: Insulin glulisine presents rapid, dose‐proportional absorption, resulting in saturable glucodynamic activity in subjects with type 1 diabetes.     

An open-label, randomized, cross-over bioequivalence study of lafutidine 10 mg under fasting condition

AIM: To assess the relative bioavailability and pharmacokinetic properties of two formulations (test and reference) of Lafutidine 10 mg.METHODS: The study was performed as an open label, randomized, two-way, two-period, two-treatment, single dose cross-over bioequivalence study, under non-fed condition to compare the pharmacokinetic profiles of the lafutidine formulation manufactured by Emcure Pharmaceuticals Ltd., India using an indigenously developed active pharmaceutical ingredient (API) and the commercially available Stogra^® formulation, of UCB Japan Co., Ltd., Japan. The two treatments were separated by a wash-out period of 5 d. After an overnight fasting period of 10 h, the subjects were administered either the test or the reference medication as per the randomization schedule. Blood samples were collected at intervals up to 24 h, as per the approved protocol. Concentrations of lafutidine in plasma were analyzed by a validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) method, and a non-compartmental model was used for pharmacokinetic analysis. The pharmacokinetic parameters were subjected to a 4-way ANOVA accounting for sequence, subjects, period and treatment. Statistical significance was evaluated at 95% confidence level (P ≥ 0.05).RESULTS: The mean (± SD) values of the pharmacokinetic parameters (test vs reference) were C_max (265.15 ± 49.84 ng/mL vs 246.79 ± 29.30 ng/mL, P < 0.05), Area under the curve (AUC)_(0-t) (1033.13 ± 298.74 ng.h/mL vs 952.93 ± 244.07 ng.h/mL, P < 0.05), AUC_(0-∞) (1047.61 ± 301.22 ng.h/mL vs 964.21 ± 246.45 ng.h/mL, P < 0.05), and t_½(1.92 ± 0.94 h vs 2.05 ± 1.01 h, P < 0.05). The 90% confidence intervals (CI) for the test/reference ratio of mean C_max, AUC_(0-t), and AUC_(0-∞) were within the acceptable range of 80.00 to 125.00. The mean times (± SD) to attain maximal plasma concentration (t_max) of lafutidine were 0.95 ± 0.24 h vs 1.01 ± 0.29 h (P < 0.05) for the test and the reference formulations respectively. Both the formulations were well tolerated.CONCLUSION: In summary, this study has demonstrated the bioequivalence of the two formulations of lafutidine 10 mg. Hence it can be concluded that the two formulations can be used interchangeably in clinical settings.     

Pharmacokinetics and Safety of Olmesartan Medoxomil in Combination with Glibenclamide in Healthy Volunteers

Objective. To investigate the pharmacokinetic interactions, safety, and tolerability of the combination of olmesartan medoxomil with glibenclamide. Methods. In an open, three-way crossover, phase I trial, 18 healthy adults entered three randomly ordered, seven-day treatment periods. The three treatments comprised once daily administration of () olmesartan 20 mg, () olmesartan 20 mg plus glibenclamide 3.5 mg, or () glibenclamide 3.5 mg. Results. The combination of olmesartan with glibenclamide did not influence the bioequivalence of the area under the plasma-concentration time curve at steady state during one dosing interval 0 to τ = 24 hours (AUC_ss,τ) or the maximum steady-state concentration (C_ss,max) of both substances. Mean AUC_ss,τ values for olmesartan were 2594.8 ng h/ml for olmesartan alone and 2443.7 ng h/ml in combination with glibenclamide; the corresponding C_ss,max values were 479.3 ng/ml and 462.7 ng/ml, respectively. For glibenclamide, the mean AUC_ss,τ values were 525.7 ng·h/ml for monotherapy and 518.7 ng·h/ml for its combination with olmesartan. The median time to reach C_ss,max (t_max) for glibenclamide was shifted from 2.0 h to 1.0 h when combined with olmesartan, whereas the median t_max values for olmesartan remained unchanged at 1.5 h. During combined treatment with olmesartan plus glibenclamide, no adverse event occurred, and the medications were well tolerated. Conclusion. With the exception of a slight shift of t_max values for glibenclamide, the concomitant administration of olmesartan medoxomil with glibenclamide had no significant effects on the steady-state pharmacokinetics of either agent. This provides the pharmacokinetic rationale for clinical studies to test the combination therapy of patients with hypertension and type-2 diabetes mellitus with both compounds.     

Pharmacokinetics of anti‐tuberculosis drugs in Venezuelan children younger than 16 years of age: supportive evidence for the implementation of revised WHO dosing recommendations

Objectives The World Health Organization (WHO) recently issued revised first‐line antituberculosis (anti‐TB) drug dose recommendations for children, with dose increases proposed for each drug. No pharmacokinetic data are available from South American children. We examined the need for implementation of these revised guidelines in Venezuela. Methods Plasma isoniazid, rifampicin, pyrazinamide and ethambutol concentrations were assessed prior to and at 2, 4 and 8 h after intake of TB drugs by 30 TB patients aged 1–15 years. The effects of dose in mg/kg, age, sex, body weight, malnutrition and acetylator phenotype on maximum plasma drug concentrations (C_max) and exposure (AUC_0‐24) were determined. Results 25 patients (83%) had an isoniazid C_max below 3 mg/l and 23 patients (77%) had a rifampicin C_max below 8 mg/l. One patient (3%) had a pyrazinamide C_max below 20 mg/l. The low number of patients on ethambutol (n = 5) precluded firm conclusions. C_max and AUC_0‐24 of all four drugs were significantly and positively correlated with age and body weight. Patients aged 1–4 years had significantly lower C_max and AUC_0‐24 values for isoniazid and rifampicin and a trend to lower values for pyrazinamide compared to those aged 5–15 years. The geometric mean AUC_0‐24 for isoniazid was much lower in fast acetylators than in slow acetylators (5.2 vs. 12.0, P < 0.01). Conclusion We provide supportive evidence for the implementation of the revised WHO pediatric TB drug dose recommendations in Venezuela. Follow‐up studies are needed to describe the corresponding plasma levels that are achieved by the recommended increased doses of TB drugs.     

The pharmacodynamic equivalence of levothyroxine and liothyronine: a randomized,double blind,cross‐over study in thyroidectomized patients

Context The substitution of liothyronine (L‐T3) for levothyroxine (L‐T4) is commonly employed during thyroid hormone (TH) withdrawal in preparation for diagnostic and therapeutic interventions on thyroid cancer patients. Presently, only limited data are available on the L‐T3 for L‐T4 therapeutic substitution. Objective To characterize the pharmcodynamic equivalence of L‐T3 and L‐T4. Design Randomized, double‐blind, cross‐over intervention study. Setting NIH clinical center. Patients Ten thyroidectomized patients. Interventions Study participants were treated with L‐T3 or L‐T4 with a target TSH ≥ 0·5 ≤ 1·5 mU/l for at least 30 days before undergoing inpatient testing. Following testing, subjects crossed‐over according to the same scheme. Main outcome measures Area under the serum concentration–time curve of TSH from 0 to 60 min (AUC_0–60) and peak TSH serum concentration (C_max) following thyrotropin‐releasing hormone (TRH) stimulation test, total L‐T4 and L‐T3 dose (mcg/kg), and L‐T4/L‐T3 ratio. Results No difference was observed for time 0 TSH values between L‐T3 and L‐T4 replacement phases (1·48 ± 0·77 vs. 1·21 ± 0·62 mU/l, P = 0·293) at average daily doses of 40·3 ± 11·3 mcg L‐T3 and 115·2 ± 38·5 mcg L‐T4, L‐T3: L‐T4 ratio 0·36 ± 0·06. TRH stimulation test resulted in similar L‐T3 vs. L‐T4 TSH responses with AUC_0–60 of 326·1 (95% CI 232·6–457·1) and 247·1 (95% CI 153·8–397·1) mU* min/l (P = 0·285); and C_max of 6·83 (95% CI 4·88–9·55) and 5·23 (95% CI 3·31–8·3) mU/l (P = 0·383). Conclusions This is the first study addressing the equivalency between L‐T3 and L‐T4 therapy measured by baseline and TRH‐stimulated TSH. The therapeutic substitution of L‐T3 for L‐T4 was achieved at approximately 1:3 ratio.     

Differential effects of once‐weekly glucagon‐like peptide‐1 receptor agonist dulaglutide and metformin on pancreatic β‐cell and insulin sensitivity during a standardized test meal in patients with type 2 diabetes

This substudy of the AWARD‐3 trial evaluated the effects of the once‐weekly glucagon‐like peptide‐1 receptor agonist, dulaglutide, versus metformin on glucose control, pancreatic function and insulin sensitivity, after standardized test meals in patients with type 2 diabetes. Meals were administered at baseline, 26 and 52 weeks to patients randomized to monotherapy with dulaglutide 1.5 mg/week (n = 133), dulaglutide 0.75 mg/week (n = 136), or metformin ≥1500 mg/day (n = 140). Fasting and postprandial serum glucose, insulin, C‐peptide and glucagon levels were measured up to 3 h post‐meal. β‐cell function and insulin sensitivity were assessed using empirical variables and mathematical modelling. At 26 weeks, similar decreases in area under the curve for glucose [AUC_glucose (0–3 h)] were observed among all groups. β‐cell function [AUC_insulin/AUC_glucose (0–3 h)] increased with dulaglutide and was unchanged with metformin (p ≤ 0.005, both doses). Dulaglutide improved insulin secretion rate at 9 mmol/l glucose (p ≤ 0.04, both doses) and β‐cell glucose sensitivity (p = 0.004, dulaglutide 1.5 mg). Insulin sensitivity increased more with metformin versus dulaglutide. In conclusion, dulaglutide improves postprandial glycaemic control after a standardized test meal by enhancing β‐cell function, while metformin exerts a greater effect on insulin sensitivity.     

Pharmacokinetic and pharmacodynamic study of ipragliflozin in Japanese patients with type 2 diabetes mellitus: A randomized,double-blind,placebo-controlled study

Aims

Ipragliflozin is a novel and highly selective sodium–glucose transporter 2 (SGLT2) inhibitor that reduces plasma glucose levels by enhancing urinary glucose excretion in patients with type 2 diabetes mellitus (T2DM). We examined the pharmacokinetic and pharmacodynamic characteristics of two oral doses of ipragliflozin in Japanese patients with T2DM.

Methods

In this randomized, placebo-controlled, double-blind study, patients were treated with placebo, 50 mg or 100 mg ipragliflozin once daily for 14 days. Plasma and urine pharmacodynamic parameters were measured on Days −1 and 14, and pharmacokinetic parameters on Day 14. Pharmacodynamic characteristics included area under the curve (AUC) for plasma glucose and insulin for 0–3 h (AUC_0–3h) and 0–24 h (AUC_0–24h). Pharmacokinetic characteristics included AUC_0–24h, maximum ipragliflozin concentration (C_max), and time to maximum plasma ipragliflozin concentration (t_max).

Results

Thirty patients were enrolled; 28 were included in pharmacokinetic/pharmacodynamic analyses and 30 in safety analyses. Administration of 50 and 100 mg ipragliflozin significantly reduced fasting plasma glucose, as well as the AUC_0–3h and AUC_0–24h for plasma glucose relative to placebo. Both doses of ipragliflozin also reduced AUC_0–24h for insulin, body weight, and glycoalbumin, while urinary glucose excretion increased remarkably. C_max and AUC_0–24h were 1.7- and 1.9-fold higher, respectively, in the 100-mg group than in the 50-mg group.

Conclusions

Ipragliflozin increased urinary glucose excretion and improved fasting and postprandial glucose, confirming its pharmacokinetic/pharmacodynamic properties in Japanese patients with T2DM.     

Safety and pharmacokinetics of the oral iron chelator SP‐420 in β‐thalassemia

Our phase I, open‐label, multi‐center, dose‐escalation study evaluated the pharmacokinetics (PK) of SP‐420, a tridentate oral iron chelating agent of the desferrithiocin class, in patients with transfusion dependent β‐thalassemia. SP‐420 was administered as a single dose of 1.5 (n = 3), 3 (n = 3), 6 (n = 3), 12 (n = 3), and 24 (n = 6) mg/kg or as a twice‐daily dose of 9 mg/kg (n = 6) over 14‐28 days. There was a near dose‐linear increase in the mean plasma SP‐420 concentrations and in the mean values for C_max and AUC_0‐τ over the dose range evaluated. The median t_max ranged from 0.5 to 2.25 h and was not dose dependent. The study was prematurely terminated by the sponsor due to renal adverse events (AE) including proteinuria, increase in serum creatinine, and one case of Fanconi syndrome. Other adverse effects included hypersensitivity reactions and gastrointestinal disturbances. Based on current dose administration, the renal AE observed outweighed the possible benefits from chelation therapy. However, additional studies assessing efficacy and safety of lower doses or less frequent dosing of SP‐420 over longer durations with close monitoring would be necessary to better explain the findings of our study and characterize the safety of the study drug.     

Amustaline (S‐303) treatment inactivates high levels of Chikungunya virus in red‐blood‐cell components

Background and objectives

Chikungunya virus (CHIKV) infections have been reported in all continents, and the potential risk for CHIKV transfusion‐transmitted infections (TTIs) was demonstrated by the detection of CHIKV RNA‐positive donations in several countries. TTIs can be reduced by pathogen inactivation (PI) of blood products. In this study, we evaluated the efficacy of amustaline and glutathione (S‐303/GSH) to inactivate CHIKV in red‐blood‐cell concentrates (RBCs).

Material and Methods

Red‐blood‐cells were spiked with high level of CHIKV. Infectious titres and RNA loads were measured before and after PI treatment. Residual CHIKV infectivity was also assessed after five successive cell culture passages.

Results

The mean CHIKV titres in RBCs before inactivation was 5·81 ± 0·18 log₁₀ 50% tissue culture infectious dose (TCID₅₀)/mL, and the mean viral RNA load was 10·49 ± 0·15 log₁₀ genome equivalent (GEq)/mL. No CHIKV TCID was detected after S‐303 treatment nor was replicative CHIKV particles and viral RNA present after five cell culture passages of samples obtained immediately after S‐303 treatment.

Conclusion

Chikungunya virus was previously shown to be inactivated by the PI technology using amotosalen and ultraviolet A light for the treatment of plasma and platelets. This new study demonstrates that S‐303/GSH can inactivate high titres of CHIKV in RBCs.     

Establishment of a Blood Purification System for Renal Failure Rats Using Small‐Size Dialyzer Membranes

Hemodialysis techniques for small animals have not been established because no small dialysis apparatus has been available. We recently developed a small‐size dialyzer and established an appropriate blood purification system for small animals. To confirm the appropriate dialysate flow rate, bovine blood was dialyzed for 60 min at a fixed blood flow rate of 1.0 mL/min and variable dialysate flow rates. Blood urea nitrogen and creatinine levels decreased significantly at a dialysate flow rate of 5 mL/min (from 13.7 ± 0.2 to 10.3 ± 1.2 mg/dL and 1.07 ± 0.15 to 0.61 ± 0.12 mg/dL, respectively, P < 0.05). To determine the appropriate in vivo conditions, extracorporeal circulation was performed in anesthetized male Sprague‐Dawley rats at a dialysate flow rate of 0.0 mL/min, for 240 min, and at variable blood flow rates. Extracorporeal circulation was successful at a blood flow rate of 1.0 mL/min, but not 1.5 mL/min. To establish in vivo hemodialysis conditions, we used the animal model of end stage renal failure. Sprague‐Dawley rats were fed a 0.75% adenine‐containing diet for 3 weeks, after which they received hemodialysis for 120 min at a dialysate and blood flow rate of 5.0 and 1.0 mL/min, respectively. There were no significant changes in systolic blood pressure or heart rate during dialysis. Thus, this blood purification system can be safely used for small animals at a dialysate flow rate of 5.0 mL/min and a blood flow rate of 1.0 mL/min. This system provides a basis for further research on hemodialysis therapy.     

The effect of hemodialysis on cycloserine, ethionamide, para-aminosalicylate, and clofazimine.

STUDY OBJECTIVES: Determine hemodialysis clearances of the second-line antitubercular drugs cycloserine (CS), ethionamide (ETA), para-aminosalicylate (PAS), and clofazimine (CFZ). DESIGN: Open-label, pharmacokinetic study SETTING: Outpatient long-term hemodialysis unit PARTICIPANTS: Eight long-term hemodialysis patients Interventions: Single oral doses of CS, 500 mg, ETA, 500 mg, PAS, 4,000 mg, and CFZ, 200 mg, were given 2 h (4 h for PAS) prior to hemodialysis (median blood flow rate, 400 mL/min; median dialysate flow rate, 600 mL/min; median hemodialysis time, 3.5 h). MEASUREMENTS AND RESULTS: Arterial and venous serum samples were collected at the beginning and end of hemodialysis, and hourly during hemodialysis. Dialysate fluid was collected for the duration of hemodialysis. All samples were assayed for drug concentrations using validated high-performance liquid chromatography (for ETA and PAS), capillary electrophoresis (for CS), and colorimetry (for CFZ). Dialysate samples were analyzed for acetyl-PAS. Median recoveries of drug in dialysate were 56% (CS), 2.1% (ETA), 6.3% (PAS parent compound), and 0% (CFZ) of the doses administered. Acetyl-PAS was dialyzed to a greater extent than its parent compound. Median hemodialysis clearances calculated by dividing the amount recovered in dialysate by the serum area under the curve during dialysis were 189 (CS), 58 (ETA), 206 (PAS), and 0 (CFZ) mL/min. CONCLUSIONS: ETA, CFZ, and PAS were not significantly dialyzed. CS is significantly removed by hemodialysis and should be dosed after hemodialysis.     

Single‐dose euglycaemic clamp studies demonstrating pharmacokinetic and pharmacodynamic similarity between MK‐1293 insulin glargine and originator insulin glargine (Lantus) in subjects with type 1 diabetes and healthy subjects

Aims

MK‐1293 is an insulin glargine that has an amino acid sequence identical to that of Lantus, the originator insulin glargine. Two euglycaemic clamp studies, 1 in subjects with type 1 diabetes (T1D) and 1 in healthy subjects, were conducted to demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) similarity between MK‐1293 and Lantus commercially procured in both the European Union (EU‐Lantus) and the USA (US‐Lantus).

Materials and Methods

Both studies were single‐dose, randomized, double‐blind, single‐centre, crossover studies with ≥7 days between dosing periods. A 2‐treatment, 4‐period replicate crossover study in T1D subjects (N = 76) compared the PK and PD of MK‐1293 to EU‐Lantus for 30 hours after dosing. A 3‐period crossover study in healthy subjects (N = 109) compared the PK and PD of MK‐1293, EU‐Lantus and US‐Lantus for 24 hours after dosing. In both studies, all subjects received single 0.4 units/kg subcutaneous doses of MK‐1293 or Lantus in all dosing periods. Pharmacokinetic assessment was based on LC‐MS/MS‐based measurement of the major insulin glargine metabolite (M1) and PD was characterized using the euglycaemic clamp platform.

Results

In both studies, pre‐specified similarity criteria were met between MK‐1293 and Lantus for comparison of PK (AUC_0‐24 and C_max of M1) and PD (GIR‐AUC_0‐24, GIR‐AUC_0‐12, GIR‐AUC_12‐24, and GIR_max) primary endpoints. All treatments were well tolerated.

Conclusion

Based on comparative assessment in both T1D and healthy subjects, it can be concluded that the PK and PD properties of MK‐1293 are highly similar to those of Lantus. (ClinicalTrials.gov: NCT02059174).     

Pharmacokinetic and tolerability profile of twice-daily saquinavir hard gelatin capsules and saquinavir soft gelatin capsules boosted with ritonavir in healthy volunteers

Objective

To evaluate the pharmacokinetics and safety of a boosted saquinavir (SQV)/ritonavir (RTV) combination, administered as either the hard gelatin capsule (HGC) or soft gelatin capsule (SGC) formulation of SQV, in 24 healthy volunteers.

Methods

This was a single‐centre, open‐label, randomized, 2 × 2 crossover study. Twelve subjects were randomized to receive SQV/RTV 1000 mg/100 mg twice daily (BID) orally for 10 days, as either the HGC or SGC formulation. The pharmacokinetic profile of SQV was determined on day 10. Subjects then crossed over to the opposite SQV formulation, and the pharmacokinetic profile was determined again on day 20. The primary analysis was the assessment of bioequivalence based on logarithmically transformed values for AUC_{(0?24 h)} and C_max for the two formulations.

Results

There was a statistically significant increase in the geometric means of all the pharmacokinetic variables evaluated for SQV‐HGC/RTV compared with SQV‐SGC/RTV. A mean AUC_{0?24 h}‐value of 15.798 µg/mL/h was reported for the HGC formulation compared with 11.655 µg/mL/h for the SGC formulation (P = 0.0043). The SQV‐HGC/RTV combination was better tolerated in terms of gastrointestinal system disorders. Furthermore, no elevations in triglycerides or total cholesterol were reported with SQV/RTV during the entire study period.

Conclusion

In healthy volunteers, RTV boosting of SQV‐HGC produces plasma exposures at least comparable to SQV‐SGC, which is accompanied by an improvement in gastrointestinal system disorders.

     

Multiple doses of pegylated long‐acting growth hormone are well tolerated in healthy male volunteers and possess a potential once‐weekly treatment profile

Objectives Recombinant human growth hormone (rhGH) replacement therapy in children and adults currently requires daily subcutaneous injections for several years or lifelong. The current study examined safety, tolerability, pharmacokinetic and pharmacodynamic response parameters after single and multiple doses of a long‐acting rhGH preparation (NNC126‐0083). Design Randomized, double‐blinded, placebo‐controlled, multiple‐dose, dose‐escalating (0·02, 0·04, 0·08 and 0·16 mg protein/kg), sequential dose group trial. Subjects Forty adult Japanese healthy male volunteers (aged 20–45; body mass index: 18·0–27·0 kg/m²). Five groups (n = 8) were randomized to receive multiple doses of NNC126‐0083 (n = 6) or placebo (n = 2). Methods Primary outcome was safety, and tolerability of multiple doses of NNC126‐0083 compared with placebo. Blood samples for the assessment of pharmacokinetics (PK) and pharmacodynamics response [insulin‐like growth factor I (IGF‐I) and IGF binding protein 3 (IGFBP‐3)] were taken after multiple ascending doses. Results NNC126‐0083 was well tolerated and not associated with any local injection‐site reactions or lipoatrophy. Following administration, NNC126‐0083 levels increased rapidly and remained elevated for several days, returning to baseline before each weekly injection. Steady‐state PK was achieved after the third dosing. A more than dose‐proportional exposure was observed at the highest NNC126‐0083 dose (0·16 mg protein/kg). A strong dose‐dependent pharmacodynamic response in circulating concentrations of both IGF‐I and IGFBP‐3 compared with placebo (P < 0·0001) was observed during the administration of all doses. Conclusions Multiple administration of NNC126‐0083 in healthy male volunteers indicates that NNC126‐0083 has the potential for an efficacious, well‐tolerated, once‐weekly rhGH compound in the treatment of GH deficiency.     

The Observed Effect of Gastric Bypass Surgery on Direct-acting Antiviral Treatment: a Case Report

Chronic hepatitis C virus (HCV) infection can be cured with treatment using direct-acting antivirals (DAAs). Although these drugs have been widely studied, information about certain special populations is missing. In this case report we describe a treatment-experienced patient with chronic HCV infection genotype 1b, treated with 150 mg/day simeprevir, 400 mg/day sofosbuvir, and 1,000 mg/ day ribavirin for 24 weeks, after a Roux-and-Y gastric bypass. At steady-state a pharmacokinetic curve was recorded of sofosbuvir, GS-331007, and simeprevir. Ribavirin trough plasma concentration (C_trough) was determined. The simeprevir area under the-concentration time curve (AUC_last) and C_trough were 9.42 h.mg/L and 0.046 mg/L, respectively. Compared to what was described in the literature, simeprevir exposure was low and therefore the simeprevir dose was increased to 300 mg/day. The increased dose of simeprevir was well tolerated and C_trough was 0.532 mg/L. Sofosbuvir AUC_last and C_trough were 0.63 h.mg/L and 0.0013 mg/L. GS-331007 AUC_last and C_trough were 21.02 h.mg/L and 0.35 mg/L. Ribavirin Ctrough was 2.5 mg/L. Sofosbuvir, GS-331007, and ribavirin exposure were comparable with levels described in literature. The patient achieved a sustained virological response twelve weeks after the completion of treatment.     

Effects of a Single,High Oral Dose of 25‐Hydroxycholecalciferol on the Mineral Metabolism Markers in Hemodialysis Patients

Vitamin D deficiency is common in dialysis patients with chronic kidney disease. Low levels have been associated with increased cardiovascular risk and mortality. We evaluated the administration of a high, single oral dose of 25‐OH cholecalciferol (3 mg of Hidroferol, 180 000 IU) in patients on chronic hemodialysis. The 94 chronic hemodialysis patients with vitamin D deficiency 25 (OH)D <30 ng/mL included in the study were randomized into two groups. Follow‐up time was 16 weeks. Neither the usual treatment for controlling Ca/P levels nor the dialysis bath (calcium of 2.5 mEq/L) were modified. Of the 86 patients who finished the study, 42 were in the treated group and 44 in the control group. An increase in 25(OH)D levels was observed in the treated group that persisted after 16 weeks and was associated with a significant decrease in parathyroid hormone (PTH) levels during the 8 weeks post‐treatment. Baseline 1,25(OH)₂D levels of the treated group increased two weeks after treatment (5.9 vs. 21.9 pg/mL, P < 0.001) but gradually reduced to 8.4 at week 16. The administration of a single 3 mg dose of 25‐OH cholecalciferol seems safe in patients on hemodialysis and maintains sufficient levels of 25(OH)D with a decrease in PTH for 3 months.     

The pharmacokinetics,safety, and tolerability of single,high-strength doses of fluticasone propionate and fluticasone propionate/salmeterol delivered via a novel multidose dry powder inhaler in adolescents and adults with persistent asthma

Objective: Characterize fluticasone propionate (Fp) and combination fluticasone propionate and salmeterol (FS) pharmacokinetic and safety profiles, delivered via a novel, inhalation-driven, multidose dry powder inhaler (MDPI). Methods: This multicenter, open-label, four-period crossover, single-dose study randomized patients aged ≥12 years with persistent asthma to Fp MDPI 200 mcg, FS MDPI 200/12.5 mcg, Fp dry powder inhaler (DPI) 500 mcg (250 mcg × 2 inhalations), or FS DPI 500/50 mcg. Blood samples for determination of Fp and salmeterol pharmacokinetic parameters including C_max, AUC_0–t, AUC_0–inf, t_max, and t_½ were collected predose through 36 h postdose (14 time points). Safety assessments comprised adverse events, vital signs, and physical examinations. The institutional review board approved the study protocol. Results: The pharmacokinetic analysis set and safety population each included 40 patients. Fp systemic exposure (C_max, AUC_0–t, and AUC_0–inf) was highest for Fp DPI 500 mcg and similar for Fp MDPI 200 mcg, FS MDPI 200/12.5 mcg, and FS DPI 500/50 mcg. Fp geometric mean t_½ values were similar across treatments. Salmeterol C_max was 20% lower and AUC_0–t and AUC_0–inf were approximately 50% lower with FS MDPI versus FS DPI. Median t_max and geometric mean t_½ were similar between FS MDPI and FS DPI. Adverse events were similar across treatments with no relevant changes in vital signs, physical examinations, or hematology test results. Conclusions: Fp MDPI and FS MDPI produced similar or lower systemic exposure to Fp and salmeterol, despite lower doses, versus conventional DPI devices, suggesting improved efficiency due to formulation and device differences.