Steady‐state amprenavir and tenofovir pharmacokinetics after coadministration of unboosted or ritonavir‐boosted fosamprenavir with tenofovir disoproxil fumarate in healthy volunteers

Objective

An open‐label, three‐period pharmacokinetic study was conducted to investigate the drug interaction potential between fosamprenavir (FPV) and tenofovir disoproxil fumarate (TDF).

Methods

Thirty‐six healthy subjects received TDF 300 mg once daily (qd) for 7 days (period 1), and then were randomized to 14 days of either FPV 1400 mg twice daily (bid) or FPV/ritonavir (RTV) 700/100 mg bid alone or with TDF (period 2). Subjects continued their randomized dose of FPV for 14 more days, adding or removing TDF based upon its receipt in period 2 (period 3). Twenty‐four‐hour pharmacokinetic sampling was carried out on day 7 of period 1 and on day 14 of periods 2 and 3. Steady‐state plasma amprenavir (APV) and tenofovir (TFV) pharmacokinetics were assessed by noncompartmental analysis and parameter values observed with each regimen were compared using geometric mean ratios with 90% confidence intervals.

Results

After TDF coadministration, APV geometric mean minimum concentration (C_min), maximum concentration (C_max), and area under the plasma concentration–time curve (AUC) increased by 31, 3 and 7% above values observed with unboosted FPV alone; they also increased by 31, 4 and 16% above values observed with FPV/RTV alone. TFV C_min, C_max and AUC decreased by 12, 25 and 15% after FPV coadministration and by 9, 18 and 7% after FPV/RTV coadministration. No significant changes in RTV pharmacokinetics were observed. No differences were noted in adverse events among dosing periods.

Conclusions

In this evaluation of the interaction between FPV and TDF, increases in APV exposures and modest decreases in TFV exposures were observed. These were unlikely to be clinically significant.

     

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.     

Effects of Laropiprant,a Selective Prostaglandin D2 Receptor 1 Antagonist,on the Pharmacokinetics of Rosiglitazone

Laropiprant (LRPT), a prostaglandin D₂ receptor‐1 antagonist shown to reduce niacin‐induced flushing symptoms, has been combined with niacin for treatment of dyslipidemia. This open‐label, randomized, 2‐period crossover study assessed the pharmacokinetics of single‐dose rosiglitazone in the presence and absence of multiple‐dose LRPT. Twelve healthy male and female subjects, 34–64 years of age, received two, once‐daily oral treatments in random sequence separated by ≥3‐day washout: (1) multiple‐dose LRPT 40 mg/day for 7 days (Days 1 to 7) coadministered with single‐dose rosiglitazone 4 mg on Day 6; (2) single‐dose rosiglitazone 4 mg on Day 1. Comparability was declared because the 90% confidence interval (CI) for the AUC_0‐∞ geometric mean ratio (GMR; rosiglitazone + LRPT/rosiglitazone alone) [0.92 (0.86, 0.99)], was contained within prespecified bounds (0.70, 1.43). The C_max GMR (90% CI) for rosiglitazone was 0.98 (0.95, 1.02). There was no evidence of clinically meaningful alterations in the pharmacokinetics of rosiglitazone, a probe CYP2C8 substrate, following coadministration of multiple‐dose LRPT in healthy subjects. Therefore, findings suggest that LRPT does not inhibit CYP2C8‐mediated metabolism.     

Safety and exposure of once-daily ritonavir-boosted atazanavir in HIV-infected pregnant women

Objective

There are limited antiretroviral options for use in the treatment of HIV infection during pregnancy. The purpose of this study was to assess the safety, efficacy and appropriate dosing regimen for ritonavir (RTV)‐boosted atazanavir in HIV‐1‐infected pregnant women.

Methods

In this nonrandomized, open‐label study, HIV‐infected pregnant women were dosed with either 300/100 mg (n=20) or 400/100 mg (n=21) atazanavir/RTV once‐daily (qd) in combination with zidovudine (300 mg) and lamivudine (150 mg) twice daily in the third trimester. Pharmacokinetic parameters [maximum observed plasma concentration (C_max), trough observed plasma concentration 24 hour post dose (C_min) and area under concentration‐time curve in one dosing interval (AUC_τ)] were determined and compared with historical values (300/100 mg atazanavir/RTV) for HIV‐infected nonpregnant adults (n=23).

Results

At or before delivery, all mothers achieved HIV RNA <50 HIV‐1 RNA copies/mL and all infants were HIV DNA negative at 6 months of age. The third trimester AUC_τ for atazanavir/RTV 300/100 mg was 21% lower than historical data, but the C_min values were comparable. The C_min value for atazanavir/RTV 400/100 mg was 39% higher than the C_min for atazanavir/RTV 300/100 mg in historical controls, but the AUC_τ values were comparable. Twice as many patients in the 400/100 mg group (62%) had an increase in total bilirubin (>2.5 times the upper limit of normal) as in the 300/100 mg group (30%). Atazanavir (ATV) was well tolerated with no unanticipated adverse events.

Conclusions

In this study, use of atazanavir/RTV 300/100 mg qd produced C_min comparable to historical data in nonpregnant HIV‐infected adults. When used in combination with zidovudine/lamivudine, it suppressed HIV RNA in all mothers and prevented mother‐to‐child transmission of HIV‐1 infection. During pregnancy, the pharmacokinetics, safety and efficacy demonstrated that a dose adjustment is not required for ATV.     

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.     

Effect of saxagliptin on the pharmacokinetics of the active components of Ortho‐Cyclen®, a combined oral contraceptive containing ethinyl estradiol and norgestimate,in healthy women

Saxagliptin (Onglyza?) is a dipeptidyl peptidase‐4 (DPP4) inhibitor for treating type 2 diabetes mellitus. This open‐label, randomized, two‐way crossover study in 20 healthy female subjects investigated the effect of saxagliptin on the pharmacokinetics (PK) of the active components of a combined oral contraceptive (COC). Subjects received either COC (Ortho‐Cyclen^®) once daily (QD) for 21 days, then 5 mg saxagliptin QD + COC QD for 21 days, or vice versa. Coadministration of saxagliptin and COC did not alter the steady‐state PK of the primary active oestrogen (ethinyl estradiol) or progestin (norelgestromin) COC components. The area under the concentration–time curve (AUC) and peak plasma concentration (C_max) of an active metabolite of norelgestromin (norgestrel) were increased by 13 and 17%, respectively, a magnitude that was not considered clinically meaningful. Coadministration of saxagliptin and COC in this study was generally well‐tolerated. Saxagliptin can be co‐prescribed with an oestrogen/progestin combination for women taking oral contraceptive.     

Co-administration of liraglutide with insulin detemir demonstrates additive pharmacodynamic effects with no pharmacokinetic interaction

Aim: To compare the pharmacokinetic (PK) [area under the curve (AUC_{0–24 h}, C_max)] and pharmacodynamic (PD) (AUC_{GIR 0–24 h}, GIR_max) properties of single‐dose insulin detemir in the presence or absence of steady‐state liraglutide (1.8 mg dose) in subjects with type 2 diabetes to determine whether co‐administration affected the PK and PD profiles of either therapeutic agent. Methods: Following a 3‐week washout of oral antidiabetic agents (OADs) other than metformin, PK and PD assessments during three euglycaemia clamps were conducted: day 1 following a single dose of insulin detemir alone (0.5 U/kg), day 22 after 3 weeks of once‐daily liraglutide with weekly dose escalation to 1.8 mg daily, and day 36 after 2 weeks of steady‐state liraglutide maintenance at the 1.8 mg dose following co‐administration with a single dose of insulin detemir (0.5 U/kg). Results: The study population (N = 33; age 49.6 (±8.5) years) had diabetes for an average of 6.5 (±4.1) years, BMI 33 (±6.4) kg/m², FPG 9.7 (±1.6) mmol/l and HbA1c 8.3% (±0.9). PK: The PK profiles of insulin detemir were similar with and without steady‐state liraglutide. Liraglutide did not affect AUC or C_max of insulin detemir and vice versa. The 90% confidence intervals (CIs) for ratios of insulin detemir AUC [1.03; CI (0.97, 1.09)] and C_max [1.05; CI (0.98, 1.13)] and liraglutide AUC [0.97; CI (0.87, 1.08)] and C_max [1.03, CI (0.93, 1.13)] were all within the no‐effect boundary (0.80, 1.25) (bioequivalence criterion). A stable mean insulin detemir concentration with and without liraglutide was maintained at the end of the 24‐h PK sampling period. PD: The sum of AUC_GIR for liraglutide (1982 mg/kg) and insulin detemir (1058 mg/kg) when given alone was similar to that obtained when the two were co‐administered (2947 mg/kg). No serious adverse events were reported and no adverse events led to study withdrawal. Conclusion: Co‐administration of liraglutide 1.8 mg at steady state and insulin detemir produces an additive glucose‐lowering effect without affecting the PK profile of either therapeutic agent suggesting that the addition of insulin detemir to patients treated with liraglutide will not require titration algorithms different from when insulin is added to OADs. The co‐administration of insulin detemir and liraglutide was well tolerated.     

Evaluation of the pharmacokinetics and pharmacodynamics of ticagrelor co-administered with aspirin in healthy volunteers

The results of two independent, randomized, two-period crossover, single-center studies, conducted to assess the pharmacokinetics of ticagrelor?±?aspirin, inhibition of platelet aggregation (IPA) with ticagrelor/aspirin vs. clopidogrel/aspirin, and safety, tolerability, and bleeding times are reported here. In Study A (open-label), 16 volunteers received ticagrelor (50?mg bid Days 1–5; 200?mg bid Days 6–9; one 200?mg dose on Day 10)?±?300?mg qd aspirin (Days 1–10). In Study B (double-blind, double-dummy), 16 volunteers received aspirin (300?mg loading dose/75?mg qd Days 2–9) with either ticagrelor (200?mg bid Days 4–8, one 200?mg dose on Day 9) or clopidogrel (300?mg loading dose Day 4, 75?mg qd Days 5–9). At steady-state ticagrelor (50?mg bid, or 200?mg bid), concomitant aspirin (300?mg qd) had no effect on mean maximum plasma concentration (C_max), median time to C_max (t_max), or mean area under the plasma concentration-time curve for the dosing interval (AUC_0–τ) for ticagrelor and its primary metabolite, AR-C124910XX. Following 200?mg bid ticagrelor, mean C_max and AUC_0–τ for both parent and metabolite were comparable with co-administration of aspirin at 75?mg and 300?mg qd. Aspirin (300?mg qd) had no effect on IPA (ADP-induced) by ticagrelor. However, aspirin and ticagrelor had an additive effect on IPA (collagen-induced). Ticagrelor/aspirin increased bleeding times vs. baseline. Ticagrelor/aspirin co-administration was well tolerated at all dose combinations evaluated. In summary, the findings of this study demonstrate that co-administration of aspirin (300?mg qd) with ticagrelor (50?mg bid, or 200?mg bid) had no effect on ticagrelor pharmacokinetics or IPA (ADP-induced) by ticagrelor.     

Effect of renal impairment and haemodialysis on the pharmacokinetics of gemigliptin (LC15‐0444)

This study evaluated the effects of renal impairment (RI) and haemodialysis (HD) on the pharmacokinetics of gemigliptin, a novel dipeptidyl peptidase‐4 (DPP‐4) inhibitor. After a 100 mg administration to subjects with normal renal function (n = 23) or RI (n = 24), plasma, urine or dialysate samples were analysed. Control subjects were matched to patients based on age, gender and body mass index. Patients with mild, moderate, severe RI and end‐stage renal disease (ESRD) showed 1.20, 2.04, 1.50 and 1.66‐fold (1.10, 1.49, 1.22 and 1.21‐fold) increase of mean area under the time‐plasma concentration curve from 0 to infinity (AUC_inf) [maximum plasma concentration (C_max)] of gemigliptin, respectively. Pharmacokinetics of gemigliptin was comparable between HD and non‐HD periods in ESRD patients. Less than 4% of the dose was removed by 4 h HD. RI appeared to have modest effect on the gemigliptin disposition. No dose adjustment in patients with RI is proposed on the basis of exposure–response relationship. Impact of HD on the removal of gemigliptin was negligible.     

Saxagliptin, a potent, selective inhibitor of DPP-4, does not alter the pharmacokinetics of three oral antidiabetic drugs (metformin, glyburide or pioglitazone) in healthy subjects

Aim: To evaluate the pharmacokinetic interactions of the potent, selective, dipeptidyl peptidase‐4 inhibitor, saxagliptin, in combination with metformin, glyburide or pioglitazone. Methods: To assess the effect of co‐administration of saxagliptin with oral antidiabetic drugs (OADs) on the pharmacokinetics and tolerability of saxagliptin, 5‐hydroxy saxagliptin, metformin, glyburide, pioglitazone and hydroxy‐pioglitazone, analyses of variance were performed on maximum (peak) plasma drug concentration (C_max), area under the plasma concentration–time curve from time zero to infinity (AUC_∞) [saxagliptin + metformin (study 1) and saxagliptin + glyburide (study 2)] and area under the concentration–time curve from time 0 to time t (AUC) [saxagliptin + pioglitazone (study 3)] for each analyte in the respective studies. Studies 1 and 2 were open‐label, randomized, three‐period, three‐treatment, crossover studies, and study 3 was an open‐label, non‐randomized, sequential study in healthy subjects. Results: Co‐administration of saxagliptin with metformin, glyburide or pioglitazone did not result in clinically meaningful alterations in the pharmacokinetics of saxagliptin or its metabolite, 5‐hydroxy saxagliptin. Following co‐administration of saxagliptin, there were no clinically meaningful alterations in the pharmacokinetics of metformin, glyburide, pioglitazone or hydroxy‐pioglitazone. Saxagliptin was generally safe and well tolerated when administered alone or in combination with metformin, glyburide or pioglitazone. Conclusions: Saxagliptin can be co‐administered with metformin, glyburide or pioglitazone without a need for dose adjustment of either saxagliptin or these OADs.     

Effects of Multiple Doses of Clarithromycin on the Pharmacokinetics of Laropiprant in Healthy Subjects

Laropiprant is a selective antagonist of the prostaglandin D₂ receptor subtype 1, and is primarily eliminated via glucuronidation with a minor contribution from oxidative metabolism via CYP3A. The effects of multiple oral doses of clarithromycin on the pharmacokinetics of laropiprant were investigated in an open‐labeled, randomized, 2‐period cross‐over study. A single oral dose of 40 mg laropiprant was administered alone or coadministered with 500 mg clarithromycin b.i.d. on Day 5 of a 7‐day clarithromycin regimen. Geometric mean ratios (90% confidence intervals) for AUC_0‐∞ and C_max of laropiprant in the presence versus absence of clarithromycin were 1.39 (1.19, 1.62) and 1.46 (1.17, 1.80), respectively. No statistically significant differences were observed in T_max (P= 0.543) or apparent terminal half‐life (P= 0.502) of laropiprant, which implies that the effect of clarithromycin on laropiprant is largely a first‐pass rather than a systemic effect. The results of this study suggest that laropiprant is not a sensitive CYP3A substrate, and strong CYP3A inhibitors like clarithromycin are not expected to have a clinically meaningful impact on the pharmacokinetics of laropiprant.     

Pharmacokinetics of emtricitabine, didanosine and efavirenz administered once-daily for the treatment of HIV-infected adults (pharmacokinetic substudy of the ANRS 091 trial)

Objective This study was conducted to investigate the pharmacokinetics of emtricitabine (FTC), didanosine (ddI), and efavirenz (EFV) when administered in a once‐daily combination. Methods Nine antiretroviral‐naïve HIV‐infected adults who received FTC [200 mg once a day (qd)], ddI (400 mg qd if ≥60 kg; 250 mg qd if <60 kg) and EFV (600 mg qd) were studied. The following pharmacokinetic (PK) parameters were determined over 24 h at steady‐state after 4 weeks of treatment: area under the plasma concentration vs. time curve (AUC_{0–24 h}), maximum (C_max) and minimum (C_min) plasma concentrations, time to reach C_max (T_max), and the elimination half‐life (t_1/2). EFV plasma concentrations were also measured during follow‐up. Results Median PK parameters for FTC, ddI and EFV, respectively, were as follows. AUC_{0–24 h}: 7.2, 7.0 and 36.4 h×mg/L; C_max: 1.8, 2.6 and 2.5 mg/L; C_min: 0.04, < 0.01 and 1.0 mg/L; T_max: 1.8, 1.1 and 2.5 h; t_1/2: 7.4, 2.3, and 23.7 h. EFV plasma concentrations measured 10–13 h postdosing were higher during follow‐up than during the PK study (2.57 vs. 1.19 mg/L, P<0.01). Conclusion The simultaneous administration of FTC, ddI and EFV did not affect the PK parameters of FTC when compared to historical controls. EFV C_max and C_min were lower than expected, but the data may have been slightly underestimated in this study. High ddI AUC and C_max were measured in these patients, and further studies are warranted to confirm this finding.     

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.     

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.     

Pharmacokinetics of tacrolimus co‐administered with adefovir dipivoxil to liver transplant recipients

Background: Adefovir dipivoxil has activity against wild‐type and lamivudine‐resistant hepatitis B virus (HBV) and is frequently used to manage HBV infection in transplant recipients. Calcineurin inhibitors are a central component of immunosuppressive therapy. Aims: Study GS‐02‐531 was an open‐label, multicentre drug interaction trial to examine potential drug interactions between adefovir and tacrolimus in stable post‐transplant recipients. Materials and Methods: Sixteen non‐HBV‐infected post‐transplant recipients with median age 45.5 years (69% male, 44% Caucasian, 50% Hispanic and 6% Black) and stable hepatic and renal function on a stable daily dose of tacrolimus (2–10 mg total daily dose) were studied before (tacrolimus alone) and after co‐administration of adefovir 10 mg daily for 14 days (Days 1–14). Pharmacokinetic (PK) analyses utilized non‐compartmental methods. Results: The median elimination half‐life of tacrolimus was 14.47 and 12.59 h for Day 0 and Day 14 respectively. The geometric mean ratios for tacrolimus on Day 14 vs Day 0 were 105.2% [90% confidence interval (90% CI): 89.8–123%] for C_max and 106.4% (90% CI: 92.9–122%) for AUC_tau. Both 90% CIs for the ratios were contained within the predefined lack of interaction bounds of 80 and 125% (i.e. within the bounds for the equivalence assessment), indicating that these PK parameters of tacrolimus are not significantly altered by co‐administration of adefovir. Similarly, the observed adefovir PK parameters after 14 days of co‐administration with tacrolimus were comparable to historical data in non‐transplant patients receiving adefovir alone. Serum creatinine values were stable during the study period. Conclusion: There is no significant PK interaction between tacrolimus and adefovir co‐administered to liver transplant recipients for 14 days.     

Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus

The hepatitis C virus protease inhibitor telaprevir is an inhibitor of the enzyme cytochrome P450 3A, responsible for the metabolism of both cyclosporine and tacrolimus. This Phase I, open-label, nonrandomized, single-sequence study assessed the effect of telaprevir coadministration on the pharmacokinetics of a single dose of either cyclosporine or tacrolimus in two separate panels of 10 healthy volunteers each. In Part A, cyclosporine was administered alone as a single 100-mg oral dose, followed by a minimum 8-day washout period, and subsequent coadministration of a single 10-mg oral dose of cyclosporine with either a single dose of telaprevir (750 mg) or with steady-state telaprevir (750 mg every 8 hours [q8h]). In Part B, tacrolimus was administered alone as a single 2-mg oral dose, followed by a minimum 14-day washout period, and subsequent coadministration of a single 0.5-mg dose of tacrolimus with steady-state telaprevir (750 mg q8h). Coadministration with steady-state telaprevir increased cyclosporine dose-normalized (DN) exposure (DN_AUC(0-∞)) by approximately 4.6-fold and increased tacrolimus DN_AUC(0-∞) by approximately 70-fold. Coadministration with telaprevir increased the terminal elimination half-life (t(?)) of cyclosporine from a mean (standard deviation [SD]) of 12 (1.67) hours to 42.1 (11.3) hours and t(?) of tacrolimus from a mean (SD) of 40.7 (5.85) hours to 196 (159) hours. CONCLUSION: In this study, telaprevir increased the blood concentrations of both cyclosporine and tacrolimus significantly, which could lead to serious or life-threatening adverse events. Telaprevir has not been studied in organ transplant patients; its use in these patients is not recommended because the required studies have not been completed to understand appropriate dose adjustments needed for safe coadministration of telaprevir with cyclosporine or tacrolimus, and regulatory approval has not been obtained.     

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).     

Subcutaneous Injection Depth Does Not Affect the Pharmacokinetics or Glucodynamics of Insulin Lispro in Normal Weight or Healthy Obese Subjects

Background:

An 8-mm needle length is commonly used for insulin injections; however, recent recommendations suggest shorter needles may help patients avoid intramuscular injections and reduce pain, while maintaining adequate glucose control. The goal of these analyses was to compare the pharmacokinetics (PK) and glucodynamics (GD) of insulin lispro after a 5-mm or an 8-mm injection depth administration in 2 populations: normal weight (study 1) or obese (study 2).

Methods:

In both open-label, randomized, 2-period crossover euglycemic clamp studies, subjects received single 0.25 U/kg insulin lispro doses on 2 occasions (at 5-mm and 8-mm injection depths); samples for PK and GD analyses were collected up to 6 hours postdose. Noncompartmental PK parameters AUC_0-tlast, AUC_0-∞, C_max and GD parameters G_tot, R_max, t_Rmax were log-transformed prior to analysis using a mixed effects model.

Results:

There were no apparent differences between PK profiles at the 5-mm or 8-mm injection depth in either study, demonstrated by the ratios of geometric means of AUC_0-tlast, AUC_0-∞, and C_max being close to 1, with 90% confidence intervals (CI) within (0.80, 1.25). There were no apparent differences between GD profiles at either injection depth with the ratios of G_tot and R_max near unity and 90% CIs that included 1. In both studies, the t_Rmax values were similar between injection depths, with a small median of pairwise differences and a 90% CI that included zero.

Conclusions:

Injection depths in the 5-8 mm range did not affect the PK or GD of insulin lispro in normal weight or obese subjects.     

Evaluation of the pharmacokinetic equivalence and 54-week efficacy and safety of CT-P13 and innovator infliximab in Japanese patients with rheumatoid arthritis

Objectives. To demonstrate the pharmacokinetic equivalence of CT-P13 and its innovator infliximab (IFX) in Japanese patients with rheumatoid arthritis (RA), and to compare the efficacy and safety of these drugs, administered for 54 weeks.

Methods. In a randomized, double-blind, parallel-group, multicenter study, 3 mg/kg of CT-P13 or IFX, in combination with methotrexate (MTX) (6–16 mg/week), was administered for 54 weeks to Japanese active RA patients with an inadequate response to MTX, to demonstrate the pharmacokinetic equivalence, based on the area under the curve (AUC_τ) (weeks 6–14) and C_max (week 6) of these drugs, and to compare their efficacy and safety.

Results. The CT-P13-to-IFX ratios (90% confidence intervals) of the geometric mean AUC_τ and C_max values in patients negative for antibodies to infliximab at week 14 were 111.62% (100.24–124.29%) and 104.09% (92.12–117.61%), respectively, demonstrating the pharmacokinetic equivalence of these drugs. In the full analysis set, CT-P13 and IFX showed comparable therapeutic effectiveness, as measured by the American College of Rheumatology, Disease Activity Score in 28 joints, the European League Against Rheumatism, and other efficacy criteria, at weeks 14 and 30. The incidence of adverse events was similar for these drugs.

Conclusion. CT-P13 and IFX, administered at a dose of 3 mg/kg in combination with MTX to active RA patients, were pharmacokinetically equivalent and comparable in efficacy and safety.     

Phase I and pharmacokinetic clinical trial of oral administration of the acyclic retinoid NIK‐333

Aim: NIK‐333 (an acyclic retinoid) has been reported to prevent recurrence of hepatocellular carcinoma (HCC) in patients after curative treatment. This study was conducted to determine the maximum tolerated dose, dose‐limiting toxicities (DLT) and pharmacokinetics of NIK‐333 administrated p.o. at doses ranging 300–900 mg/day. Methods: Patients who were cancer‐free after percutaneous local ablation or surgical resection of HCC were enrolled. The total daily dose was administrated as a single dose (single‐dose stage) followed by a week of rest, and then in two equally divided doses administrated after breakfast and supper for 48 consecutive weeks (repeated‐dose stage). Results: No patients at the dose levels of 300 mg/day and 600 mg/day developed any DLT. At the final dose level of 900 mg/day, three of the nine patients developed grade 3 hypertension as a DLT. There were no significant difference values of maximum drug concentration (C_max) and log(C_max) between fasting and postprandial condition. In the repeated‐dose stage, there was no significant difference between the start and week 24 of NIK‐333 administration within any dose cohort in either the mean area under the blood concentration time curve (0–6 h) or the C_max. NIK‐333 was well‐tolerated when administrated p.o. at doses of up to 600 mg/day for 48 weeks. Conclusion: Hypertension was noted as a DLT at the dose level of 900 mg/day, and this dose was considered to be inappropriate. The recommended dose for the phase II/III clinical trial is thought to be 300 mg/day and 600 mg/day.