Biological characteristics of lactosaminated N-succinyl-chitosan as a liver-specific drug carrier in mice.

Lactosaminated N-succinyl-chitosan (Lac-Suc) was prepared by reductive amination of N-succinyl-chitosan (Suc) and lactose using sodium cyanoborohydride. Six-day reaction using lactose (12.8-fold (w/w)) yielded Lac-Suc with lactosamination degree of 30% (mol/sugar unit). Fluorescein thiocarbamyl-Lac-Suc (Lac-Suc-FTC) was prepared by labeling Lac-Suc with fluorescein isothiocyanate. Lac-Suc-FTC was injected intravenously at a dose of either 1 (high dose) or 0.2 (low dose) mg/mouse. At both doses, Lac-Suc-FTC initially underwent fast hepatic clearance, showed maximum liver localization at 8 h, and the amounts localized there were maintained even at 48 h post-injection. Very slow excretion into feces and urine was observed. The ratio of liver AUC_{0–48 h} to plasma AUC_{0–48 h} at low dose was three times higher than that at high dose. On the other hand, the Suc derivative, Gal-Suc, obtained by reductive amination of Suc/galactose showed very little distribution to the liver similarly to Suc itself. Further, since the liver uptake of Lac-Suc-FTC was inhibited by asialofetuin, it was suggested that the liver distribution of Lac-Suc should be concerned with asialoglycoprotein receptor. Thus, Lac-Suc was found available as a carrier exhibiting a high affinity to and long retention in the liver.     

The effect of pharmacokinetic/pharmacodynamic (PK/PD) parameters of gatifloxacin on its bactericidal activity and resistance selectivity against clinical isolates of Streptococcus pneumoniae

The impact of the pharmacokinetic/pharmacodynamic (PK/PD) parameters (the 24h area under the concentration-time curve [AUC_24h]/minimum inhibitory concentration [MIC] and maximum concentration in serum [C_max]/MIC ratio) after single oral dosing of gatifloxacin on its bactericidal activity and resistance selectivity against quinolone-susceptible clinical isolates of Streptococcus pneumoniae J-69 was investigated using an in vitro PK model. The MICs of gatifloxacin, levofloxacin, and ciprofloxacin were 0.25, 1, and 1µg/ml, respectively. When the range of AUC_24h/MIC ratios was varied from 9.0 to 36 with a constant C_max/MIC ratio of 3.4, the bactericidal activity was correlated with the AUC_24h/MIC ratios. Eradication was observed at an AUC_24h/MIC ratio of 36. On the other hand, the resistance selectivity was associated with the C_max/MIC ratio. Mutant strains were selected at a C_max/MIC ratio of 0.84, but not 1.7 with a constant AUC_24h/MIC ratio of 9.0. These results suggested that an AUC_24h/MIC ratio of 36 and a C_max/MIC ratio of 1.7 might be possible benchmarks to show enough bacterial eradication and prevention of emergence of resistant strains to gatifloxacin, respectively. When the serum concentrations after clinical oral dosing of gatifloxacin (200mg b.i.d.), levofloxacin (100mg t.i.d.), and ciprofloxacin (200mg t.i.d.) were simulated, the bactericidal activity of gatifloxacin was higher than those of levofloxacin and ciprofloxacin. Moreover, no resistant strain was obtained by the exposure to gatifloxacin and levofloxacin, whereas ciprofloxacin selected resistant strains. The clinically relevant oral dosage of gatifloxacin was anticipated to result in a high AUC_24h/MIC₉₀ ratio of 81 and a C_max/MIC₉₀ ratio of 4.4, suggesting that this agent is clinically effective in the treatment of pneumococcal infections.     

Pharmacodynamic comparison of two formulations of Acarbose 100-mg tablets

What is known and Objective: Acarbose, an α‐glycosidase inhibitor, is used to treat diabetic patients. Pharmacokinetic evaluation of acarbose is difficult because <2% is absorbed systemically. The current investigation evaluated the bioequivalence of two formulations of acarbose through pharmacodynamic comparison. Methods: This investigation consisted of a pilot study and a main study. The pilot study had an open, single‐dose, single‐sequence design. Subjects received placebo and then two tablets of reference formulation (Glucobay^® 100 mg tablet; Bayer Healthcare) on two consecutive days with sucrose. The main study was an open, randomized, two‐period, two‐sequence crossover study. Subjects randomly received placebo and two tablets of either test formulation (generic acarbose 100‐mg tablet) or reference formulation with sucrose on two consecutive days in the first period. In the second period, placebo and alternative formulation were administered. Serial blood samples for pharmacodynamic assessment were taken after each administration. The maximum serum glucose concentration (G_max) and the area under the serum glucose concentration–time profile (AUC_gluc) were determined and compared. Results and Discussion: Five subjects completed the pilot study. The AUC_gluc from dosing until 1 h post‐dose (AUC_{gluc,1 h}) was significantly different between the placebo and acarbose. A total of 33 subjects completed the main study. The mean differences in G_max (ΔG_max) and AUC_{gluc,1 h} (ΔAUC_{gluc,1 h}) for the reference formulation compared with placebo were 22·0 ± 18·3 mg/dL and 928·2 ± 756·0 mg min/dL, respectively. The corresponding values for the test formulation were 23·3 ± 21·2 mg/dL and 923·0 ± 991·4 0 mg min/dL, respectively. The geometric mean ratios (GMRs) of the test formulation to the reference formulation for ΔG_max and ΔAUC_{gluc,1 h} were 1·06 and 1·00, respectively, and the 90% confidence intervals (CIs) corresponding values were 0·79–1·39 and 0·64–1·36, respectively. What is new and Conclusion: The 90% CIs of GMRs for the pharmacodynamic parameters chosen for bioequivalence evaluation of two formulations of acarbose did not meet the commonly accepted regulatory criteria for bioequivalence (0·80–1·25).     

Pharmacodynamic evaluation of tosufloxacin against Streptococcus pneumoniae in an in vitro model simulating serum concentration

We compared the antibacterial effects and the emergence of resistance to tosufloxacin or levofloxacin for Streptococcus pneumoniae by simulating the serum concentration according to the Japanese clinical regimens using an in vitro pharmacokinetic-pharmacodynamic model. For quinolone-susceptible strain ATCC49619, tosufloxacin showed bactericidal activity, given that both the AUC_0–24h/MIC ratios at the dosage of 150 mg t.i.d. and 300 mg b.i.d. of tosufloxacin tosilate were 138 and 193, and the C_max/MIC ranges were 7.93–10.2 and 15.9–17.6, respectively, which were greater than those of levofloxacin (100 mg t.i.d. and 200 mg b.i.d.). The greater area above the killing curves (AAKCs) or shorter time to achieve 99.9% killing (99.9% KT) in both models of tosufloxacin than those of levofloxacin was related to their larger AUC_0–24h/MIC and C_max/MIC. Exposure of only 100 mg t.i.d. of levofloxacin led to outgrowth of the parC mutants, which were twofold less susceptible to levofloxacin than the parent strain. Neither of the tosufloxacin tosilate regimens resulted in isolation of resistant mutants of this strain. For the parC mutant strain D-3197, both the AUC_0–24h/MIC and C_max/MIC ratios of tosufloxacin were greater than those of levofloxacin, which resulted in comparable or better bactericidal activity as compared to those of levofloxacin. However, both fluoroquinolones and both regimens led to outgrowth of resistant mutants, which possessed a mutation in gyrA in addition to parC. In conclusion, tosufloxacin is superior to levofloxacin in bactericidal activity against S. pneumoniae in the Japanese clinical regimens, especially in the quinolone-susceptible strain, without emergence of resistant subpopulations.     

Effect of soybean administration on the pharmacokinetics of carbamazepine and omeprazole in rats

Influence of soybean administration on the bioavailability of carbamazepine and omeprazole was studied after single dose administration of soybean (10 g/kg p.o.) or after chronic administration of soybean (50% w/w mixed with normal feed) for 15 days in rats. Carbamazepine was administered orally at a dose of 10 mg/kg and omeprazole at a dose of 20 mg/kg. Soybean decreased the bioavailability of carbamazepine after both single dose and chronic administration. It produced a significant decrease in C_max, T_max, AUC_0–t of carbamazepine after single dose administration and increased the plasma clearance and V_d along with decrease in C_max, T_max, AUC_0–t and AUC_{0– ∞} after chronic administration. On the contrary, soybean administration increased the bioavailability of omeprazole by producing an increase in C_max, AUC_0–t and AUC_{0– ∞} and a decrease in V_d after single dose administration and a decrease in plasma clearance along with increase in C_max, AUC_0–t and AUC_{0– ∞} after chronic administration. The half‐life of omeprazole was also increased after both acute and chronic administration of soybean. It was concluded that soybean decreases the bioavailability of carbamazepine and increases the bioavailability of omeprazole after both single dose and chronic administration.     

Effects of clarithromycin on the pharmacokinetics of tacrolimus and expression of CYP3A4 and P-glycoprotein in rats

The objective of this study was to investigate the effect of clarithromycin on the pharmacokinetics of tacrolimus in rats and better understand its mechanism. In the control group (n = 6), rats received a single oral dose of 1 mg tacrolimus on day 6. In the experimental group (n = 6), rats received 0.25 g of clarithromycin daily for five consecutive days and then a single oral dose of 1 mg tacrolimus on day 6. Orbital venous blood (250 μL) was collected at 0, 0.25, 0.50, 0.75, 1, 2, 4, 8, 12, and 24 h before and after tacrolimus administration. Blood drug concentrations were detected via mass spectrometry. Small intestine and liver tissue samples were collected after rats were euthanized via dislocation, and CYP3A4 and P-glycoprotein (P-gp) protein expression was determined using western blotting. Clarithromycin increased the blood tacrolimus concentration and affected its pharmacokinetic properties in rats. Compared with those in the control group, the AUC_0–24, AUC_0–∞, AUMC_(0–t), and AUMC_(0–∞) of tacrolimus in the experimental group were significantly increased, whereas the CLz/F was significantly lower (P < 0.01). Simultaneously, clarithromycin significantly inhibited CYP3A4 and P-gp expression in the liver and intestine. Protein expression of CYP3A4 and P-gp in the liver and the intestinal tract was significantly downregulated in the intervention group compared with that in the control group. Clarithromycin significantly inhibited the protein expression of CYP3A4 and P-gp in the liver and intestine, thereby increasing the mean blood concentration and significantly increasing the AUC of tacrolimus.     

Telavancin pharmacokinetics and pharmacodynamics in patients with complicated skin and skin structure infections and various degrees of renal function

This study characterized the pharmacokinetic/pharmacodynamic profiles of the Food and Drug Administration (FDA)-approved telavancin renal dose adjustment schemes. A previously published two-compartment open model with first-order elimination and a combined additive and proportional residual error model derived from 749 adult subjects in 11 clinical trials was used to simulate the individual concentration-time profiles for 10,260 subjects (NONMEM). The dosing regimens simulated were 10 mg/kg of body weight once daily for individuals with creatinine clearances (CL_CRs) of >50 ml/min, 7.5 mg/kg once daily for individuals with CL_CRs of 30 to 50 ml/min, and 10 mg/kg every 2 days for those with CL_CRs of <30 ml/min. The area under the concentration-time curve (AUC) under one dosing interval (AUC_τ) was computed as dose/CL. The probability of achieving an AUC_τ/MIC ratio of ≥219 was evaluated separately for each renal dosing scheme. Evaluation of the dosing regimens demonstrated similar AUC values across the different renal function groups. For all renal dosing strata, >90% of the simulated subjects achieved an AUC_τ/MIC ratio of ≥219 for MIC values as high as 2 mg/liter. For patients with CL_CRs of <30 ml/min, the probability of target attainment (PTA) exceeded 90% for both the AUC_0–24 (AUC from 0 to 24 h) and AUC_24–48 intervals for MICs of ≤1 mg/liter. At a MIC of 2 mg/liter, the PTAs were 89.3% and 23.6% for the AUC_0–24 and AUC_24–48 intervals, respectively. The comparable PTA profiles for the three dosing regimens across their respective dosing intervals indicate that the dose adjustments employed in phase III trials for complicated skin and skin structure infections were appropriate.     

Comparative pharmacokinetics of Panadol Extend and immediate-release paracetamol in a simulated overdose model

Background: Panadol Extend is a modified‐release paracetamol formulation in which each 665 mg tablet contains 69% slow‐release and 31% immediate‐release paracetamol. There are no data on Panadol Extend pharmacokinetics in overdose. It is unknown whether the paracetamol treatment nomogram can be used to make decisions regarding the toxicity of this product in overdose. Objective: To compare the pharmacokinetics of Panadol Extend and immediate‐release paracetamol (APAP‐IR) in simulated overdose model in healthy volunteers. Methods: Cross‐over study using a dose of 90 mg/kg ideal body weight of Panadol Extend or APAP‐IR in seven healthy volunteers. Serum paracetamol concentrations were measured over 12 h. Maximal paracetamol concentration (Cmax), time to Cmax (Tmax), area under the curve (AUC) and elimination half‐life (t_1/2) were compared. Results: Mean paracetamol dose was 73 mg/kg actual body weight. Panadol Extend produced lower Cmax (0.208 mmol/L ± 0.02 vs 0.48 mmol/L ± 0.02, P = 0.0001) and AUC_{0?12 h} when compared with APAP‐IR. Tmax was delayed with Panadol Extend (2.83 h ± 0.26 vs 0.94 h ± 0.17, P = 0.0001). Absorption was complete in all subjects by 4 h post ingestion in both study arms. Elimination t_1/2 was 1.69 ± 0.09 h for APAP‐IR and 1.65 ± 0.13 h for Panadol Extend (not significant). Conclusions: Reductions in Panadol Extend Cmax and AUC_{0?12 h} might be related to elimination occurring during the absorption phase. In this model of Panadol Extend moderate overdose, Tmax was significantly delayed. In larger overdoses, time to peak paracetamol levels might be further delayed, because of continuing absorption from the formulation. Therefore, the paracetamol treatment nomogram might not reliably predict hepatotoxicity from Panadol Extend if paracetamol levels are measured too early.     

Optimal levofloxacin dosing regimens in critically ill patients with acute kidney injury receiving continuous renal replacement therapy

PurposesTo determine appropriate dosing of levofloxacin in critically ill patients receiving continuous renal replacement therapy (CRRT).MethodsAll necessary pharmacokinetic and pharmacodynamic parameters from critically ill patients were obtained to develop mathematical models with first order elimination. Levofloxacin concentration-time profiles were calculated to determine the efficacy based on the probability of target attainment (PTA) of AUC_24h/MIC ≥50 for Gram-positive and AUC_24h/MIC ≥125 for Gram-negative infections. A group of 5000 virtual patients was simulated and tested using Monte Carlo simulations for each dose in the models. The optimal dosing regimens were defined as the dose achieved target PTA at least 90% of the virtual patients.ResultsNo conventional, FDA approved regimens achieved at least 90% of PTA for Gram-negative infection with Pseudomonas aeruginosa at MIC of 2 mg/L. The successful dose (1750 mg on day 1, then 1500 mg q 24 h) was far exceeded the maximum FDA-approved doses. For Gram-positive infections, a levofloxacin 750 mg q 24 h was sufficient to attain PTA target of ~90% at the MIC of 2 mg/L for Streptococcus pneumoniae.ConclusionsLevofloxacin cannot be recommended as an empiric monotherapy for serious Gram-negative infections in patients receiving CRRT due to suboptimal efficacy.     

Prophylaxis with lactoferrin,a novel antimicrobial agent,in a neonatal rat model of coinfection

Lactoferrin has broad-spectrum antimicrobial activity, and the authors hypothesized that recombinant human lactoferrin (Talactoferrin alfa [TLF]) would reduce mortality and morbidity in a coinfection model. The MIC₅₀ (minimum inhibitory concentration required to inhibit the growth of 50% of organisms) of TLF againstCandida albicans andStaphylococcus epidermidis was determined. Neonatal Wistar rats were infected withCalbicans orS epidermidis or both, at doses of 2 × 10⁸ colony-forming units (CFUs) given subcutaneously. Rat pups in each group were randomly given TLF intraperitoneally at 40 mg/kg/dose or 300 mg/kg/dose, or saline in 0.2 mL, once a day for 4 d and were monitored for mortality, weight gain, and blood culture positivity. Trough serum levels of TLF were measured at 24, 48, 72, 96, and 144 h. MIC₅₀ of TLF was 30 μg/mL and 500 μg/mL forC albicans and Sepidermidis, respectively. TLF prophylaxis significantly improved survival in the coinfection group at 40 mg/kg/dose (by 16.1%; P=.019) and at 300 mg/kg/dose (by 15.1%; P=.027) and in the Sepidermidis group at a dose of 40 mg/kg/dose (by 1 8.6%; P=.04). Weight gain was not affected by TLF prophylaxis. Serum trough levels of TLF were 1000-fold lower than in vitro MIC₅₀. The authors conclude that lactoferrin prophylaxis significantly enhanced survival in coinfection and in the subgroupof S epidermidis infection (40 mg/kg/dose) through indirect mechanisms.     

Pharmacokinetics of experimental pentavalent antimony after intramuscular administration in adult volunteers

Background:

Pentavalent antimony (SbV) has demonstrated therapeuticeffectiveness against clinical manifestations of leishmaniasis, an infection caused by Leishmania, a genus of flagellate protozoa comprising parasites of worldwide distribution. Approximately 1.8 million new cases are reported annually.

Objective:

The aim of this study was to assess the pharmacokinetics of the investigational generic SbV, Ulamina (pentachloride of antimony + N-methylglucamine), in healthy adult volunteers.

Methods:

In this study, SbV was administered IM as a single 5-mg/kg dose.Blood samples were collected at 0.25, 0.75, 1, 2, 4, 8, 12, and 24 hours after administration; urine samples were collected at 6-hour intervals during the 24-hour postadministration period. Determination of trivalent antimony, SbV, and total antimony concentrations in blood and urine samples was carried out using atomic absorption spectrometry. Clinical history was reviewed and the subjects were monitored before and after administration of SbV using physical examination, weight, and hepatic- and renal-function studies. The pharmacokinetic parameters calculated were C_max, T_max, absorption constant (Ka), elimination constant (K_el), AUC_2-24h, AUC_0-∞, elimination phase (t_½β), volume of distribution (V_d), and urinary excretion rate.

Results:

Five subjects (3 men, 2 women; mean age, 28 years [range, 18-34 years]) were included in the study. One hour after drug administration the following values were obtained: C_max, 1.1 μg/mL; T_max, 1.3 hours; Ka, 1.87 hours; K_el, 0.043 hours; AUC_0-24h, 12.26 μg/mL · h; AUC_0-∞, 19.84 μg/mL · h; t_½β, 17.45 hours; V_d, 6.6 L/kg; and urinary excretion rate, 2.8 μg/h; these were mean values for the entire study group. The single dose was well tolerated by all subjects.

Conclusions:

The investigational generic SbV, Ulamina, was associated with linearelimination after IM administration of a single 5-mg/kg dose. A 2-compartment pharmacokinetic model was observed in these volunteers; the mean t_½β, was 17.45 hours and the mean V_d was 6.6 L/kg.     

Pharmacokinetics of duloxetine hydrochloride enteric-coated tablets in healthy Chinese volunteers: A randomized,open-label,single- and multiple-dose study

Background: Duloxetine hydrochloride is a balanced selective serotonin and norepinephrine reuptake inhibitor. Despite being widely used for the treatment of major depressive disorder in China, little information is available on the pharmacokinetic (PK) properties of duloxetine in Chinese subjects.Objectives: This study was designed to determine the concentration of duloxetine in human plasma and to compare the PK properties of duloxetine after administration of single and multiple doses of duloxetine in healthy Chinese volunteers.Methods: A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determining the concentration of duloxetine in human plasma was developed and applied to this single-center, open-label, single- and multiple-dose PK study. Subjects were randomized to receive a single dose of 30, 60, or 90 mg of duloxetine. Those who received the 30-mg dose continued on to the multiple-dose phase and received 30 mg twice daily for 7 days. In the single-dose phase, sequential blood samples were collected from 0 to 60 hours after drug administration. In the multiple-dose phase, samples were obtained before drug administration on days 4, 5, 6, and 7 to determine the Cssmin of duloxetine; on day 7, samples were collected from 0 to 60 hours after drug administration. The PK parameters that were calculated included C_max, T_max, t_1/2, AUC_0?t AUC_0?∞, CL, V_d, C_ssmax, C_ssmin, C_ssav, AUC_ss, AUC_ss(0?t), and C_max:C_min ratio. All values were expressed as mean (SD). Tolerability was assessed throughout the study.Results: The LC-MS/MS method was developed and validated. The standard calibration curve was linear in the concentration range from 0.89 to 106.8 ng/mL; the correlation coefficient was >0.995. The methodo-logic recovery and extraction recovery ranged from 87.22% to 113.75% and 72.81% to 89.96%, respectively. Both the intraday and interday relative SDs were <11%. Thirty Chinese subjects (3 groups of 10 subjects [5 men, 5 women] each) were enrolled in the single-dose phase of the PK study. The mean (SD) age of the subjects was 23.2 (1.8) years (range, 21–25 years); their mean (SD) weight was 61.0 (7.7) kg (range, 52–80 kg) and height was 169.0 (7.1) cm (range, 155–180 cm). The main PK parameters for duloxetine after administration of a single oral dose of 30, 60, and 90 mg were as follows: C_max = 22.46 (15.15), 44.40 (17.18), and 60.78 (27.84) ng/mL, respectively; AUC_0–60 = 328.64 (203.64), 696.04 (337.82), and 1219.33 (598.29) ng/mL · h^?1; AUC_0?∞) = 359.68 (201.01), 733.82 (343.40), and 1280.51 (644.81) ng/mL · h^?1; T_max = 6.83 (1.99), 6.10 (1.29), and 6.60 (1.58) hours; t1/2 = 12.95 (3.64), 12.81 (2.31), and 11.66 (2.06) hours; CL = 107.90 (53.05), 98.41 (41.98), and 109.58 (52.74) L/hour; and V_d = 2518.88 (1707.71), 1879.74 (999.09), and 1858.47 (1203.69) L. The 10 subjects who received the 30-mg dose in the single-dose phase continued on to the multiple-dose phase and received 30 mg of duloxetine twice daily for 7 days. Mean (SD) values for the main PK parameters for duloxetine after administration of multiple doses were as follows: C_ssmax = 47.33 (16.95) ng/mL; C_ssmm = 27.92 (9.46) ng/mL; AUC_ss(0?t) = 407.25 (125.94) ng/mL · h^?1; C_ssav = 33.94 (13.00) ng/mL; T_max = 6.36 (0.92) hours; t_1/2 = 11.19 (1.98) hours; CL = 83.12 (28.75) L/hour; and V_d = 1359.01 (590.06) L.Conclusions: In these healthy Chinese subjects, AUC and Cmax increased proportionally with the dose, whereas t_1/2 was independent of the dose. Linear PK properties were found at doses of 30 to 90 mg. No statistically significant differences were observed between the PK parameters for the subjects in the multiple-dose phase (t_1/2, CL, V_d) and those for subjects in the single-dose phase. The AUC and C_max were greater after administration of multiple doses than after administration of a single dose, suggesting du-loxetine accumulation with multiple-dose administration of 30 mg.     

Population pharmacokinetics and pharmacodynamics of sitafloxacin in patients with community-acquired respiratory tract infections

An optimal dosage regimen of sitafloxacin was considered based on a pharmacokinetics and pharmacodynamics (PK–PD) analysis in patients with community-acquired respiratory tract infections (RTI). A population pharmacokinetic analysis of sitafloxacin was conducted using clinical data of five clinical pharmacology studies and one clinical PK–PD study in patients with RTIs. The pharmacokinetic parameters in individual patients were estimated by the Bayesian method to examine any correlation between pharmacokinetics and bacteriological efficacy. Efficacy data were obtained from the clinical PK–PD study, in which 50 or 100 mg sitafloxacin was administered twice daily for 7 days. In addition, an efficacy was simulated for a hypothetical dose regimen of 100 mg once daily. The fAUC_0–24h/MIC and the fC _max/MIC of sitafloxacin at a dose of 50 mg twice daily were 117.5 ± 78.0 and 7.3 ± 4.7 (mean ± SD), respectively. As a result of the univariate logistic regression analysis, the larger the value of fAUC_0–24h/MIC or fC _max/MIC becomes, the higher the bacteriological efficacies. The eradication rates for fAUC_0–24h/MIC ≥ 30 and for fC _max/MIC ≥ 2 were 96.4 % and 96.3 %, respectively. The PK–PD target values of sitafloxacin for the treatment of mild to moderate RTIs were considered to be fAUC_0–24h/MIC ≥ 30 and fC _max/MIC ≥ 2. The PK–PD parameters at the regimen of 50 or 100 mg twice daily in patients with RTIs reached the target values. Furthermore, a 100 mg once-daily regimen was expected to show similar efficacy based on the PK–PD simulations.     

A limited sampling strategy for estimating mycophenolic acid area under the curve in adult heart transplant patients treated with concomitant cyclosporine

Objective: Heart transplantation studies have shown a relationship between the mycophenolic acid area under the curve (AUC) 0–12 h (MPA AUC_0–12h) values and risk of acute rejection episodes and fewer side‐effects in patient receiving cyclosporine during the first year post‐transplant. However, measurement of full AUC is costly and time consuming and in this case it is an impractical approach to drug monitoring. Therefore, the authors describe a limited sampling strategy to estimate the MPA AUC_0–12h value in adult heart transplant recipients. Methods: Ninety MPA pharmacokinetic (PK) profiles were studied. The samples were collected immediately before and 0·5, 1, 1·5, 2, 2·5, 3, 4, 6, 9, 12 h after the morning dose of mycophenolate mofetil (MMF) following an overnight fast. PK profiles were determined at 6–8 weeks, 6, 12 months and more than 1 year after transplantation. Using stepwise multiple linear regression analysis a sampling strategy from 60 of PK profiles was obtained and next the bias and precision of the model were evaluated in another 30 PK profiles. Results: The three‐point model using C_0·5h, C_1h, C_2h was found to be superior to all other models tested (r² = 0·841). The regression equation for AUC estimation which gave the best fit to this model is: 9·69 + 0·63C_0·5 + 0·61C₁ + 2·20C₂. Using that model 63 of the 90 (70%) full AUC values were estimated within 15% of their actual value. For the best‐fit model, the mean prediction error was 3·2%, with 95% confidence intervals for prediction error to range from ?42·2% to 40·3%. All other models which use one, two or three time‐points over the first 2 h are poorer predictors of the full AUC than the model above. Conclusion: The proposed three time‐point equation to estimate AUC will be helpful in optimizing immunosuppressive therapy in heart transplantation.     

An initial dosing method for teicoplanin based on the area under the serum concentration time curve required for MRSA eradication

Teicoplanin is a glycopeptide antibacterial agent that has a long serum half-life and therefore takes time to achieve steady-state conditions. An appropriate initial dosing is needed for teicoplanin to promptly reach an effective serum trough concentration. However, little information is available on tailoring the initial dosing for patients with various characteristics. The objective of this study was to develop a nomogram for determining teicoplanin initial dose to promptly reach an effective trough concentration (≥13 μg/mL). A logistic regression analysis was performed to test whether the area under the concentration time curve (AUC) is a significant predictor of microbiological response (persistence 0; eradication 1). The study included 24 adult patients with methicillin-resistant Staphylococcus aureus infections [minimal inhibitory concentration (MIC) for the isolates was <2 μg/mL). Each AUC was estimated using individual dose, creatinine clearance (CL_cr), and body weight data. The target value, which gives about a 0.9 microbiological eradication probability, was 750 μg h/mL for AUC from zero to 24 h (AUC_0–24 h). Using published population pharmacokinetic parameters, the dose required to achieve the AUC_0–24 h target was calculated as dose (mg) = 750 × (0.00498 × CL_cr (mL/min) + 0.00426 × body weight (kg). For various combinations of CL_cr and body weight, we checked the calculated doses using a therapeutic drug monitoring (TDM)-supporting software and developed a nomogram. The nomogram would be useful for initial dose adjustment to promptly reach an effective serum trough concentration and avoid adverse events of teicoplanin.     

Microdose study of a P‐glycoprotein substrate,fexofenadine, using a non‐radioisotope‐labelled drug and LC/MS/MS

Objective: Fexofenadine is a P‐glycoprotein substrate of low bioavailability. It is primarily excreted into faeces as a parent drug via biliary excretion. The predictability from microdose data for the drug absorbed via transporters such as P‐glycoprotein is not known. Therefore, this study assessed the predictability of therapeutic‐dose pharmacokinetics of fexofenadine from microdosing data using non‐radioisotope‐labelled drug and liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI‐MS/MS). Method: In a single dose, randomized, two‐way crossover study, eight subjects received a microdose (100 μg) or a therapeutic dose (60 mg) of fexofenadine. Blood samples were collected until 12 h after dosing, and assayed using LC/MS/MS. Results: Plasma concentration–time curves of fexofenadine between microdose and therapeutic dose were similar. The mean ± SD of C_max normalized to 60 mg dose after microdose and therapeutic dose were 379 ± 147 and 275 ± 145 ng/mL respectively. The mean AUC_last normalized to 60 mg dose after microdose and therapeutic dose were 1914 ± 738 and 1431 ± 432 ng/h/mL respectively. The mean dose‐adjusted C_max and AUC_last after microdose were higher compared with those after therapeutic dose. Individual plots of C_max and AUC_last normalized to 60 mg dose, were similar for microdose and therapeutic dose. None of the pharmacokinetic parameters were statistically different using anova . Overall, the microdose pharmacokinetics profile was similar to, and hence predictive of, that of the therapeutic dose. Conclusion: For the P‐glycoprotein substrate fexofenadine, the predictability of therapeutic‐dose pharmacokinetics from microdose data was good. A microdose study using a non‐radioisotope‐labelled drug and LC/MS/MS is convenient, and has the potential to aid the early selection of drug candidates.     

Pharmacokinetics of a Once-Daily extended-release formulation of pramipexole in healthy male volunteers: Three studies

Background: Pramipexole is a dopamine agonist used in the treatment of Parkinson's disease. The currently available immediate-release (IR) formulation is taken orally 3 times daily.Objectives: These studies were conducted to evaluate the pharmacokinetic properties of a variety of prototypes for a once-daily extended-release (ER) formulation of pramipexole and to further characterize the prototype whose pharmacokinetics best matched those of the IR formulation.Methods: Three Phase I studies were conducted, all in healthy adult men aged ≤50 years with a body mass index of 18.5 to 29.9 kg/m². In the first study, 7 prototypes of a once-daily ER formulation with various release properties, including rate and pH dependence, were compared with the IR formulation taken 3 times daily to identify the optimal pharmacokinetic resemblance based on predefined criteria derived from plasma AUC_0?24h, C_max, and C_min. In the second study, a level A in vitro/in vivo correlation (IVIVC) suitable for predicting an entire in vivo bioavailability time course based on in vitro dissolution was established and validated, and the single-dose pharmacokinetics of the optimal ER formulation identified in the first study were analyzed for food effect. In the third study, steady-state pharmacokinetics of the optimal ER formulation were assessed across a range of pramipexole doses (0.375–4.5 mg/d), including investigation of the food effect at steady state for the highest dose. Tolerability was assessed throughout all studies based on physical examinations, laboratory measurements, and adverse events (AEs).Results: The 3 studies included 18, 15, and 39 subjects, respectively. Among the ER prototypes tested at 0.75 mg once daily in study 1, a matrix tablet had the optimal pharmacokinetic resemblance to IR pramipexole 0.25 mg TID, with a geometric mean AUC_0?24h,ss of 17.4 ng·h/mL (vs 16.0 ng·h/mL for the IR formulation), C_max,ss of 0.967 ng/mL (vs 1.09 ng/mL), and C_min,ss of 0.455 ng/mL (vs 0.383 ng/mL). For single-dose ER 0.375 mg administered in the fasted state in study 2, in vivo bioavailability was predictable from in vitro dissolution data, with internal mean absolute percent prediction errors of 3.18% for AUC_0?30h and 4.87% for C_max, and external mean absolute prediction errors of 6.61% and 3.34%, respectively, satisfying current guidelines for a level A IVIVC. For single-dose ER 0.375 mg administered in the fed state, the upper bound of the 90% CI for fed:fasted values was 119.8 for AUC_0–30h (within the bioequivalence limits of 80%–125%) and 134.1 for C_max. At steady state in study 3 (subjects' 5th treatment day), dosing at 0.375 to 4.5 mg in the fasted state was associated with a linear, dose-proportional increase in pharmacokinetic parameters, including AUC_0–24h,ss and C_max,ss. At the highest fasted dose (4.5 mg), the geometric coefficient of variation for interindividual variability at steady state was 30.1% for AUC_0–24h,ss (vs 21.4% for IR pramipexole 1.5 mg TID) and 22.3% for C_max,ss(vs 19.0%). At steady state, the upper bounds of the 90% CIs for fed:fasted values with ER 4.5 mg were 122.1 for AUC_0–24h and 126.8 for C_max. No serious AEs occurred, and the dropout rate was low.Conclusions: In these studies in healthy male volunteers, an ER pramipexole formulation was identified that resembled the IR formulation in terms of both pharmacokinetics and tolerability. In patients with Parkinson's disease, once-daily use of an ER formulation may improve the convenience of treatment relative to the IR formulation taken 3 times daily and thus increase compliance.     

Comparison of the Pharmacokinetic and Pharmacodynamic Relationship of Ipragliflozin Between Patients With Type 1 and Type 2 Diabetes Mellitus

PurposeTo characterize the pharmacokinetic and pharmacodynamic (PK/PD) relationship of ipragliflozin in Japanese patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) and to determine the appropriate dose regimen for a Phase III study of ipragliflozin in Japanese patients with T1DM.MethodsThe PK (AUC_24h of plasma ipragliflozin) and PD (renal glucose clearance) properties in patients with T1DM and T2DM were assessed in 2 independent clinical pharmacologic studies of ipragliflozin. The same maximum efficacy (E_max) model described the PK/PD relationship in patients with T1DM and T2DM. Changes in fasting plasma glucose (FPG) in T1DM patients were simulated by applying a previously established FPG model for ipragliflozin in patients with T2DM.FindingsData from 42 patients with T1DM and 28 patients with T2DM were used. Comparable AUC_24h of plasma ipragliflozin and similar dose dependency were observed on day 14 between patients with T1DM and those with T2DM. Decreases in renal glucose clearance were comparable regardless of the ipragliflozin dose in both groups of patients. The estimated mean E_max and AUC_24h producing 50% of E_max (EX₅₀) were 45.1 mL/min (95% CI, 37.0–53.2 mL/min) and 2160 ng·h/mL (95% CI, 929–3390 ng·h/mL), respectively, in all patients with T1DM and T2DM. Observed FPG in patients with T1DM was reproduced well by the simulation from the previously established FPG model.ImplicationsThe PK/PD properties for ipragliflozin were comparable between patients with T1DM and T2DM, suggesting no substantial difference in PK/PD relationships in both patient populations. The dose regimen used for patients with T2DM was also recommended for a Phase III study in Japanese patients with T1DM. ClinicalTrials.gov identifiers: NCT01023945 and NCT02529449.     

Exploration of optimal teicoplanin dosage based on pharmacokinetic parameters for the treatment of intensive care unit patients infected with methicillin-resistant Staphylococcus aureus

Severely ill intensive care unit (ICU) patients are frequently at risk of developing methicillin-resistant Staphylococcus aureus (MRSA) infections. It is generally accepted that a trough level of >10 μg/mL teicoplanin (TEC) is appropriate for most such infections. The present study was designed to determine how TEC exposure and patient characteristics affect microbiological response in the treatment of MRSA infections. All patients studied were admitted to Aichi Medical University Hospital ICU between May 2005 and April 2010. Fifty-nine patients were prescribed TEC and 33 of those patients used to treat MRSA infection. Outcome was classified as either cure or failure, and logistic regression analysis was performed to determine which covariates, including severity, significantly influenced the microbiological response. Satisfactory outcomes were obtained in 19 of the 33 patients. Although the cured and failed groups showed adequate trough concentrations, the area under the serum concentration curve (AUC_0–24) on the third day was significantly higher for the cured group (897.6 ± 71.7) than for the failed group (652.9 ± 83.4) (p < 0.05). The results suggested that at least 800 μg h/mL TEC AUC_0–24 were required to obtain microbiological cure. The higher AUC_0–24, the better the outcome. In our study, higher initial AUC_0–24 was associated with a better microbiological outcome, which demonstrates the importance of the loading dose of TEC, especially for ICU patients. Moreover, the present findings are useful for optimizing the individual dose of TEC using AUC_0–24 in the treatment of MRSA-infected patients.     

A randomized crossover study to assess the pharmacokinetics of a novel amphetamine extended-release orally disintegrating tablet in healthy adults

Objectives: In this pharmacokinetic (PK) study in healthy adults, we sought to: (1) compare the PK properties of a novel amphetamine extended-release orally disintegrating tablet formulation (Adzenys XR-ODT? [AMP XR-ODT]) to a reference extended-release mixed amphetamine salts (MAS ER) formulation and (2) assess the effect of food on AMP XR-ODT.

Methods: Forty-two adults were enrolled in a single-dose, open-label, 3-period, 3-treatment, randomized crossover study and received an 18.8-mg dose of AMP XR-ODT (fasted or fed) or equivalent dose (30 mg) of MAS ER (fasted). Plasma samples were analyzed for d-and l-amphetamine. Maximum plasma concentration (C_max), time to maximum plasma concentration (T_max), elimination half-life (T_1/2), area under the concentration-time curve from time zero to last quantifiable concentration (AUC_last), from time zero to infinity (AUC_inf), relevant partial AUCs, and weight-normalized clearance (CL/F/kg) were assessed. The PK parameters were compared across treatments using an ANOVA. Safety was also assessed.

Results: A total of 39 adults completed this study. The geometric mean ratios (90% confidence interval [CI]) for AMP XR-ODT/MAS ER C_max, AUC_5-last, AUC_last, and AUC_inf were within 80%–125% for both d-and l-amphetamine. The 90% CIs for AUC_0-5 were slightly below the 80%–125% range. When AMP XR-ODT was administered with food, there was a slight decrease in the d-and l-amphetamine C_max and approximately a 2-hour delay in T_max. The most common adverse events reported (>5% of participants) were dry mouth, palpitations, nausea, dizziness, headache, anxiety, and nasal congestion.

Conclusions: AMP XR-ODT displayed a PK profile similar to MAS ER, and no clinically relevant food effect was observed.