Tolerability of lacosamide rapid dose titration: A randomized, multicenter, prospective, open-label study.

OBJECTIVE: Currently recommended dosing of lacosamide often necessitates long titration periods. However, the use of a regimen consisting of initial loading dose of 200 mg followed by a maintenance dose of 200 mg/day in practice suggests tolerability of more rapid titration schedules. We aimed to clarify whether the shortened titration schedule affects tolerability of lacosamide. METHODS: We evaluated the safety of two rapid titration protocols designed to reach the target dose of 400 mg/day within 1 week, and the conventional weekly titration protocol (reaching the target dose of 400 mg/day in three weeks). The ≥50% responder rate and steady-state plasma concentration of lacosamide were also analyzed. Adverse events were assessed at 1 week and 5 weeks after reaching the target dose. RESULTS: Seventy-five patients with epilepsy were enrolled and evenly distributed to three titration protocols, from which 5 patients were lost to follow-up and excluded from the safety analysis. Discontinuation of lacosamide or dose reductions due to adverse events occurred in 32 patients (46%), of whom a large majority (74%) had experienced adverse events after reaching 400 mg/day, demonstrating apparent dose-dependency. There was no difference in safety outcomes among the three titration groups. Concomitant use of sodium channel blockers significantly increased the risk of adverse events. CONCLUSION: Rapid titration protocols for lacosamide were not associated with an increased risk of adverse events compared to the conventional weekly titration protocol. Uptitration of lacosamide at shorter intervals to an effective target dosage may be feasible in appropriate clinical situations.

Comparative pharmacokinetics of Theracurmin, a highly bioavailable curcumin, in healthy adult subjects.

OBJECTIVE: Theracurmin is a submicron dispersed formulation of curcumin, which was developed to increase the bioavailability of curcumin. This study aimed to compare the pharmacokinetics of curcumin administered as two Theracurmin powder products and unformulated curcumin powder. MATERIALS AND METHODS: This randomized, three-treatment, six-sequence, and three-period crossover study enrolled 24 healthy subjects. Blood sampling was done until 12 hours after the administration of Theracurmin and curcumin powder to assess pharmacokinetics using a non-compartmental method. The plasma concentration of curcumin was determined using high-performance liquid chromatography coupled with tandem mass spectrometry. RESULTS: The median time to reach the maximum concentration was 1.5 - 3 hours for Theracurmin and 8 hours for curcumin powder. The two Theracurmin products showed systemic exposure profiles that were comparable to each other. The exposure ratio of Theracurmin to curcumin powder was 18.4 - 20.5 for the maximum plasma concentration and 35.9 - 42.6 for the area under the concentration-time curve from dosing to the last measurable time. CONCLUSION: In conclusion, this study showed similar systemic exposure between the two Theracurmin products. The absorption of curcumin after the administration of Theracurmin was significantly enhanced compared with curcumin powder.

Oral absorption of voriconazole is affected by SLCO2B1 c.*396T>C genetic polymorphism in CYP2C19 poor metabolizers.

High pharmacokinetic variability of voriconazole is mainly explained by CYP2C19 phenotype, but there are still unknown factors affecting the variability. In this study, the effect of solute carrier organic anion transporter family member 2B1 (SLCO2B1) genotype on the pharmacokinetics (PKs) of voriconazole was evaluated in 12 healthy CYP2C19 poor metabolizers after a single administration of voriconazole 200 mg intravenously and orally. In addition, the influence of CYP3A4 enzyme activity was also explored. The oral absorption of voriconazole was decreased and delayed in the subjects with the SLCO2B1 c.*396T>C variant compared to the subjects with wild type. However, the CYP3A activity markers measured in this study did not show significant association with metabolism of voriconazole. The results suggest that the SLCO2B1 c.*396T>C may be associated with the decreased function of intestinal OATP2B1, and it could contribute to interindividual PK variability of voriconazole.

Safety, tolerability and pharmacokinetics and pharmacodynamics of HL2351, a novel hybrid fc-fused interleukin-1 receptor antagonist, in healthy subjects: A first-in-human study.

AIMS: We performed a first-in-human study with HL2351, a novel hybrid Fc-fused interleukin (IL)-1 receptor antagonist, to evaluate its tolerability, pharmacokinetics and pharmacodynamics (PD) after a single subcutaneous (SC) administration in healthy subjects. METHODS: A randomized, double-blind, placebo- and active-controlled, dose-escalation study was conducted. Eligible subjects randomly received a single SC administration of HL2351 (1, 2, 4, 8 and 12 mg/kg) or placebo in a ratio of 8:2. Subjects in the active-controlled group received a single SC administration of anakinra at 100 mg. Serial blood samples were collected for pharmacokinetics and PD analyses. An ex-vivo activation test was performed to evaluate the PD using peripheral blood mononuclear cells treated with IL-1ß. Anti-HL2351 antibodies were determined at baseline and 29 days postdose. Tolerability was assessed throughout the study. RESULTS: HL2351 was eliminated more slowly than anakinra (terminal half-life: 27.21-45.28 vs 3.97 h). Serum concentrations of HL2351 were increased dose-proportionally. The mean apparent clearance of HL2351 were 0.6, 0.66, 0.75, 0.51, 0.65 L/h at 1, 2, 4, 8 and 12 mg/kg, respectively. The percent inhibition of IL-6 expression varied widely (range: 0-92.1%), showing no clear trend or discernible difference between HL2351, anakinra and placebo. HL2351 was well tolerated after a single SC administration. CONCLUSION: HL2351 was well tolerated and showed linear pharmacokinetic characteristics after a single SC administration at doses up to 12 mg/kg in healthy subjects. HL2351 remained in the body 7-11 times longer than anakinra. HL2351 can be developed as a potential therapeutic alternative to anakinra.

Multiple-dose pharmacokinetics and safety of amoxicillin/clavulanate in healthy elderly subjects.

BACKGROUND: Amoxicillin/clavulanate is a widely used oral formulation of penicillin combined with a ß-lactamase inhibitor. When using amoxicillin/clavulanate in the elderly, the risk of adverse drug reaction may be greater. This study aimed to evaluate the pharmacokinetics (PKs) and safety of multiple-dose amoxicillin/clavulanate administration in healthy elderly subjects and to compare the observed PK profiles with those in healthy younger adults. An open-label, one-sequence, multiple administration study was conducted in 16 healthy elderly subjects. MATERIALS AND METHODS: Subjects orally received amoxicillin and clavulanate 750/187.5 twice daily for 9 days. For PK analysis, serial blood samples were collected up to 12 hours after the last administration of amoxicillin/clavulanate. The demographic and PK data of this study were compared to those of healthy young adults from a separate study with a similar design. Safety assessments including clinical laboratory tests, physical examination, vital signs, and adverse event (AE) monitoring were performed throughout the study. RESULTS: All AEs were mild, and no serious AEs were reported in this study. The systemic exposure of amoxicillin and clavulanate was ~ 90% and 60% higher, respectively, in the elderly subjects than in the younger subjects. However, the time required to reach maximum concentration at steady state and the elimination half-life were similar in the two age groups. CONCLUSION: Although multiple administration of amoxicillin/clavulanate 750/187.5 mg was safe and well-tolerated, the systemic exposure of amoxicillin and clavulanate was higher in elderly subjects than in younger subjects.

Population Pharmacokinetic Study of Prophylactic Fluconazole in Preterm Infants for Prevention of Invasive Candidiasis.

Fluconazole is an antifungal agent with reported evidence for its prophylactic effect against systemic fungal infection in preterm infants. The aim of this study was to build a population pharmacokinetic model to evaluate the pharmacokinetic characteristics of intravenous and oral fluconazole in preterm infants with the current prophylactic fluconazole dosing regimen. A pharmacokinetic model was developed using 301 fluconazole concentrations from 75 preterm infants with a baseline body weight (WT) ranging from 0.5 to 1.5 kg and an estimated glomerular filtration rate (eGFR) ranging from 12.9 to 58.5 ml/min/1.73 m2 Eligible infants received an intravenous or oral dose of 3 mg/kg of body weight of fluconazole, twice weekly with a ≥72-h dose interval, for 4 weeks. The model was qualified with basic goodness-of-fit diagnostics, visual predictive checks, and bootstrapping. The fluconazole pharmacokinetics was well described with a one-compartment linear model with a proportional residual error. The population clearance (CL) and volume of distribution (V) were derived as 0.0197 × (WT/1.00)0.746 × (eGFR/25.0)0.463 × exp(η) and 1.04 × WT × exp(η), respectively. Such covariate analyses augment the awareness of the need for personalized dosing in preterm infants. (This study has been registered at ClinicalTrials.gov under identifier NCT01683760).

The Genetic Polymorphism UGT1A4*3 Is Associated with Low Posaconazole Plasma Concentrations in Hematological Malignancy Patients Receiving the Oral Suspension.

The metabolism of posaconazole is mediated mainly by uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes, especially UGT1A4. The aim of this study was to investigate the effects of genetic polymorphisms on the posaconazole plasma concentration (PPC). This prospective study was conducted from September 2014 to August 2016. We enrolled patients with acute myeloid leukemia or myelodysplastic syndrome treated with posaconazole oral suspension (200 mg) three times daily for fungal prophylaxis. The patients were examined for the multidrug resistance gene 1 3435C>T and 2677G>T/A variations and the UGT1A4*3 allele by direct sequencing of DNA from peripheral whole-blood samples. We defined poor absorbers to be those with PPCs of <200 ng/ml and the optimal PPC to be ≥700 ng/ml on day 8. The associations between genetic polymorphisms and the PPC were evaluated using multivariate logistic regression analysis including clinical variables. During the study period, 132 patients were enrolled. Six patients (4.5%) were defined as poor absorbers, and 49 patients (37.1%) did not reach the optimal PPC on day 8. In multivariate analysis, the independent risk factors for a poor absorber were at least one UGT1A4*3 allele (adjusted odds ratio [aOR], 18.81; 95% confidence interval [CI], 1.09 to 324.44; P = 0.043) and poor oral food intake (aOR per -100 kcal, 1.44; 95% CI, 1.04 to 1.99; P = 0.029). There was no statistically significant association between the genetic polymorphisms and achievement of the optimal PPC on day 8. The UGT1A4*3 polymorphism is an independent risk factor for being a poor absorber of posaconazole oral suspension in patients with hematological malignancies.

Early Therapeutic Drug Monitoring of Posaconazole Oral Suspension in Patients With Hematologic Malignancies.

BACKGROUND: Therapeutic drug monitoring (TDM) of posaconazole is usually performed 1 week after starting the drug because of its long half-life. However, previous studies showed that measuring the posaconazole plasma concentration (PPC) on day 3 is effective for predicting steady-state levels. The purpose of this study was to evaluate the relevance of early TDM (day 3) of posaconazole for achieving an optimal PPC. METHODS: This prospective study was conducted from September 2014 to August 2016. A total of 148 patients with acute myeloid leukemia or myelodysplastic syndromes received a 200 mg posaconazole oral suspension 3 times daily for fungal prophylaxis. During the period from September 2014 to December 2015 (control group), no dose adjustment was performed on day 3. During the period from January 2016 to Aug 2016 (early TDM group), the frequency of posaconazole 200-mg administration was increased to 4 times daily in patients whose PPC on day 3 was <400 ng/mL. The cutoff value for optimal PPC on day 8 was defined as 500 ng/mL. RESULTS: In 21 of 107 patients (20%) in the control group, PPC was <400 ng/mL on day 3. In 15 (71%) of these 21 patients, the PPC was suboptimal on day 8. In the early TDM group, the PPC was <400 ng/mL on day 3 in 4 of 41 patients (10%). After increasing the posaconazole administration frequency in these 4 patients, PPC was suboptimal on day 8 in 1 patient (25%). In both groups, 104 patients had a PPC of ≥500 ng/mL on day 3, but 7% (7/104) of these had a suboptimal level on day 8. CONCLUSIONS: Early TDM on day 3 for posaconazole suspension may help more patients achieve optimal drug levels on day 8, although TDM on day 8 is needed even in patients with optimal levels on day 3.

Effect of food on the pharmacokinetics of YH4808, a potassium-competitive acid blocker, after single- and multiple-oral dosing in healthy subjects.

PURPOSE: YH4808 is a potassium-competitive acid blocker, developed for the treatment of acid-related disorders. Two clinical studies in healthy male subjects were conducted to evaluate the effect of food on the pharmacokinetics of YH4808. METHODS: The first study, a randomized, three-treatment, three-period, crossover study, compared pharmacokinetics of YH4808 (300 mg) after a single dose at fed state with a standard or a high-fat meal to those at fasted state. The second study, a randomized, two-treatment, two-period, crossover study, investigated pharmacokinetics at fasted or fed state with a standard meal after twice daily dose of YH4808 (100 mg) for 7 days. Bloods for pharmacokinetic evaluation were sampled up to 48 h post-dose and 24 h post-dose at steady state, respectively. The pharmacokinetic parameters were estimated by non-compartmental method. RESULTS: After single dosing, the geometric means of maximum plasma concentration increased by 1.2 and 2.1 times in the fed states with a standard meal and a high-fat meal, respectively, of that in fasted state. Corresponding values of area under the plasma concentration-time curve (AUC) from time 0 to the last measurable time point increased by 1.8 and 2.8 times, respectively. After multiple dosing, the geometric mean for 24-h AUC at steady state slightly increased in fed state by 1.1 times of that in fasted state. CONCLUSIONS: As fat content of the food increased, the systemic exposure of YH4808 after single dosing increased. However, systemic exposures at steady state after multiple dosing between fasted and fed states were similar. TRIAL REGISTRATION: ClinicalTrials.gov registry no.: NCT01520012.

Effects of renal impairment on the pharmacokinetics and pharmacodynamics of a novel dipeptidyl peptidase-4 inhibitor, evogliptin (DA-1229).

Evogliptin is a novel potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitor. The aim of the present study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of evogliptin in participants with renal impairment (RI). An open-label, parallel-group clinical study was conducted in participants with mild, moderate and severe RI and in matched participants with normal renal function (NRF). A single oral 5-mg dose of evogliptin was administered and serial blood and urine samples were obtained to assess the PK and PD characteristics of evogliptin. Baseline urine samples were collected to evaluate endogenous CYP3A metabolic markers. The plasma exposure to evogliptin and degree of DPP-4 activity inhibition increased with decreasing renal function. The mean areas under the concentration-time curves from 0 to 120 hours were increased 1.2-, 1.8- and 1.98-fold in the mild, moderate and severe RI groups, respectively, compared with the NRF group. The levels of CYP3A metabolic markers were lower in the RI group than in the NRF group. The increase in the plasma concentration of evogliptin is unlikely to result in changes in its efficacy or safety, considering the results of previous clinical studies.

Pharmacokinetic comparison using two tablets of an evogliptin/metformin XR 2.5/500 mg fixed dose combination vs. 1 tablet each of evogliptin 5 mg and metformin XR 1,000 mg
.

OBJECTIVES: The aim of this study was to compare the pharmacokinetic (PK) characteristics of evogliptin and metformin following the administration of 2 evogliptin/metformin extended-release (XR) 2.5/500 mg FDC tablets with the coadministration of separate evogliptin 5-mg and metformin XR 1,000-mg tablets (separate formulations). METHODS: A randomized, two-period, two-sequence crossover study was conducted. Subjects were randomly assigned to receive 2 FDC tablets or the individual tablets, followed by a 14-day washout period and the administration of the alternate treatment. Blood samples were collected predose and up to 72 hours postdose for each period. PK parameters including Cmax and AUClast were calculated. The geometric mean ratios (GMRs) and the 90% confidence intervals (CIs) between FDC and the separate formulations were calculated for the Cmax and AUClast of evogliptin and metformin. RESULTS: 33 subjects completed the study. The GMR (90% CI) values of Cmax and AUClast for evogliptin were 1.011 (0.959 - 1.066) and 1.010 (0.977 - 1.043), respectively. The GMR (90% CI) values of Cmax and AUClast for metformin were 0.892 (0.827 - 0.963) and 0.893 (0.841 - 0.947), respectively. There was no significant difference between the FDC and separate formulations regarding the occurrence of adverse events. All drug-related adverse events were considered to be mild and resolved without any treatment. CONCLUSIONS: Two FDC tablets of evogliptin/metformin XR 2.5/500 mg showed a similar PK profile to the separate formulations of evogliptin 5 mg and metformin XR 1,000 mg. All of the 90% CIs of GMR satisfied the regulatory bioequivalence criteria of 0.800 - 1.250.
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Effects of proton pump inhibitors on metformin pharmacokinetics and pharmacodynamics.

As inhibitors of organic cation transporters (OCTs), proton pump inhibitors (PPIs) may affect the plasma levels of metformin, an OCT substrate. We investigated the effects of two PPIs, pantoprazole and rabeprazole, on metformin pharmacokinetics and glucose levels in healthy subjects. In this open, randomized, six-sequence, three-period crossover study, 24 participants were administered metformin, either alone or in combination with pantoprazole or rabeprazole. The plasma concentrations of metformin and serum concentrations of glucose after a 75-g oral glucose tolerance test (OGTT) were determined. The area under the concentration-time curve (AUC) for metformin was 15% and 16% greater following coadministration with pantoprazole and rabeprazole, respectively. The maximum plasma metformin concentrations (Cmax) also increased by 15% and 22%, respectively, compared with when it was administered without the PPIs. The percentage change in the AUC for glucose concentration versus time for metformin plus rabeprazole was significantly lower than that for metformin plus pantoprazole [geometric mean ratio: 0.96 (90% confidence interval: 0.92-0.99) and 0.77 (0.63-0.93), respectively]. There was no significant difference in the maximum glucose concentration. In conclusion, concomitant administration of PPIs with metformin significantly increased plasma metformin exposure, but the effects on glucose disposition were minor and varied depending on the PPI administered.

Effects of HM30181, a P-glycoprotein inhibitor, on the pharmacokinetics and pharmacodynamics of loperamide in healthy volunteers.

AIMS: HM30181 is a third generation P-glycoprotein (P-gp) inhibitor currently under development. The objectives of this study were to evaluate the effects of a single dose of HM30181 on the pharmacodynamics and pharmacokinetics of loperamide, a P-gp substrate, and to compare them with those of quinidine. METHODS: Eighteen healthy male subjects were administered loperamide alone (period 1) or with loperamide plus quinidine or HM30181 in period 2 or 3, respectively. In period 3, subjects randomly received one of three HM30181 doses: 15, 60 or 180 mg. Changes in pupil size, alertness, oxygen saturation and the oral bioavailability of loperamide were assessed in each period. In addition, the pharmacokinetics of HM30181 were determined. RESULTS: Pupil size, alertness and oxygen saturation did not change over time when loperamide alone or loperamide plus HM30181 was administered while HM30181 significantly increased the systemic exposure to loperamide, i.e. the geometric mean ratio (90% confidence interval) of AUC(0,tlast ) for loperamide with and without HM30181 was 1.48 (1.08, 2.02). Co-administered quinidine significantly increased the systemic exposure to loperamide 2.2-fold (1.53, 3.18), which also markedly reduced pupil size, resulting in a decrease of 24.7 mm h in the area under the effect curve of pupil size change from baseline compared with loperamide alone. CONCLUSIONS: HM30181 inhibits P-gp mainly in the intestinal endothelium, which can be beneficial because pan-inhibition of P-gp, particularly in the brain, could lead to detrimental adverse events. Further studies are warranted to investigate adequately the dose-exposure relationship of HM30181, along with its duration of effect.

Global metabolomics and targeted steroid profiling reveal that rifampin, a strong human PXR activator, alters endogenous urinary steroid markers.

Activation of the pregnane X receptor (PXR) alters the expression of metabolic enzymes and transporters involved in the metabolism of xenobiotics and endobiotics. To identify endogenous biomarkers of PXR activation in humans, rifampin, a strong PXR activator, was administered to 12 healthy male subjects, and their urine was analyzed before and after rifampin administration. Ultraperformance liquid chromatography time-of-flight mass spectrometry (UPLC/QTOF-MS)-based global metabolomics and gas chromatography-mass spectrometry (GC-MS)-based profiling of 75 steroids were used to screen the urine samples. Global metabolomics revealed that hydroxytestosterone sulfate and glycochenodeoxycholate sulfate levels were significantly increased and that androsterone sulfate, dehydroepiandrosterone (DHEA) sulfate, and p-cresol sulfate levels were significantly decreased following rifampin administration compared with controls. Urinary steroid profiling showed that 16α-OH-androstenedione (16α-OH-A-dione), 16α-OH-DHEA, 7α-DHEA, 7ß-DHEA, and 11ß-OH-A-dione levels were increased, whereas DHEA, androsterone, etiocholanolone, estrone, ß-cortolone, and allo-tetrahydrocortisone levels were decreased in the rifampin group. The analysis of the metabolic pathway and the metabolic ratio of steroids enabled the estimation of the induction of CYP1A/3A/7B/11B/2C and the inhibition of CYP17A/19A in response to PXR activation. These human urinary biomarkers may be useful for predicting the extent of PXR activation, monitoring the activity of DMEs, and anticipating drug-drug interactions in patients administered PXR-activating drugs.

Apple juice greatly reduces systemic exposure to atenolol.

AIM: Fruit juice reduces the plasma concentrations of several ß-adrenoceptor blockers, likely by inhibiting OATP2B1-mediated intestinal absorption. The aim of this study was to investigate the effects of apple juice on the pharmacokinetics of atenolol. METHODS: Twelve healthy Korean volunteers with genotypes of SLCO2B1 c.1457C> T (*1/*1 (n = 6) and *3/*3 (n = 6)) were enrolled in this study. In a three-phase, one-sequence crossover study, the pharmacokinetics (PK) of atenolol was evaluated after administration of 50 mg atenolol. Subjects received atenolol with either 300 ml water, 1200 ml apple juice or 600 ml apple juice. RESULTS: Apple juice markedly reduced the systemic exposure to atenolol. The geometric mean ratios (95% confidence intervals) of apple juice : water were 0.18 (0.13, 0.25, 1200 ml) and 0.42 (0.30, 0.59, 600 ml) for the AUC(0,t(last)). In this study, the PK parameters of atenolol responded in a dose-dependent manner to apple juice. CONCLUSIONS: Apple juice markedly reduced systemic exposure to atenolol. The genetic variation of SLCO2B1 c.1457C>T had a minimal effect on the pharmacokinetics of atenolol when the drug was administered with water or apple juice.

Population pharmacokinetics of theophylline in premature Korean infants.

OBJECTIVES: The aim of this study was to investigate the population pharmacokinetics of theophylline in premature Korean infants and to assess the influence of clinical covariates. METHODS: Blood samples were first obtained after 1 week of maintenance dosing and then acquired approximately 4 weeks after continuous dosing. The time points were just before dosing and 2, 4, or 6 hours (at randomly assigned time points) after dosing. Two single-nucleotide polymorphism markers, -3860 G>A (CYP1A2*1C) and -163C>A (CYP1A2*1F), were genotyped. Gestational age (GA), postnatal age (PNA), postconceptional age (PCA = GA + PNA), body weight (BW), height, serum AST, serum ALT, serum BUN, serum creatinine, oxygen support, sex, delivery mode, and CYP1A2 genotypes were used for covariate model building. External validation was analyzed using data from an additional 27 patients. RESULTS: A total of 334 serum concentration measurements were made in 100 patients. A one-compartment absorptive model with first-order elimination was fitted to the data in NONMEM (version 7.1.2). The final model included the following parameters: Clearance (L/h) = 0.00492 × (BW)(3.53) + 0.00646 × (PNA), and volume of distribution (L) = 1.53 × (BW). The addition of the CYP1A2*1C or CYP1A2*1F genotypes to the model did not improve the model. The external validation results confirmed the predictive performance without bias in the final model. CONCLUSIONS: The selected covariates were generally consistent with previous studies. However, the mean volume of distribution was higher than the values reported in other population pharmacokinetic studies, which may have been due to the use of 2 sampling time points. The predictive performance was reasonably acceptable. Therefore, the present model may permit more accurate selection of doses to achieve target theophylline concentrations in premature infants.

Usefulness of oral loading of oxcarbazepine suspension in selected patients with epilepsy.

OBJECTIVES: Oral loading of oxcarbazepine tablet is effective and well tolerated to adequately achieve the therapeutic levels of its active metabolite, 10,11-dihydro-10-hydroxy-carbazepine (monohydroxy derivative, MHD) in epilepsy patients. The present study was performed to investigate the safety, tolerability, and pharmacokinetic profiles of oral loading of oxcarbazepine suspension in epilepsy patients with a high risk of recurrent seizures. METHODS: Oxcarbazepine suspension was administered orally at a single loading dose of 30 mg/kg to 38 adult patients with recurrent seizures, who required rapid seizure control or temporarily discontinued antiepileptic drugs for diagnostic or pre-surgical evaluation. Plasma concentrations of oxcarbazepine and MHD were determined, and adverse events were assessed at 2, 4, 6, 8, 10, 12, 14, 16, and 24 hours after oral loading of oxcarbazepine suspension. RESULTS: 30 patients experienced ≥ 1 adverse event during the first 24 hours after oral loading of oxcarbazepine (e.g., dizziness, transient diplopia, nausea or vomiting), most of which occurred within 4 hours after loading, suggesting no temporal association with MHD plasma levels. 35 (92.1%) patients were still compliant with a maintenance dose of oxcarbazepine after discharge from hospital. 34 (89.4%) patients reached the lower therapeutic level of MHD (12 mg/l) at 4 hours after oral loading of oxcarbazepine suspension, which lasted up to 24 hours in most patients. No patient reached the supratherapeutic levels of MHD (> 35 mg/l) during the study. The mean plasma concentration-time curves and pharmacokinetic profiles of oral loading of oxcarbazepine suspension were similar to those of oral loading of oxcarbazepine tablet. CONCLUSIONS: Oral loading of oxcarbazepine suspension followed by maintenance dosing is well tolerated and effective in steadily achieving the therapeutic level of MHD in selected patients with epilepsy.

The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in invasive fungal infections: a randomized controlled trial.

BACKGROUND: Blood levels of voriconazole, a first line therapy for invasive aspergillosis, may correlate with adverse events and treatment response. However, no randomized controlled studies have been conducted to evaluate the clinical utility of routine therapeutic drug monitoring (TDM) of voriconazole. This study aimed to determine whether routine TDM of voriconazole reduces drug adverse events or improves treatment response in invasive fungal infections. METHODS: This was a randomized, assessor-blinded, controlled, single center trial. One hundred ten adult patients were randomly assigned to TDM or non-TDM groups. In the TDM group, voriconazole dosage was adjusted (target range, 1.0-5.5 mg/L) according to the serum trough level measured on the fourth day after initiation of voriconazole. The non-TDM group received a fixed, standard dosage. Voriconazole-related adverse events were monitored, and treatment response was assessed three months after the initiation of therapy. RESULTS: Baseline characteristics including the CYP2C19 genotype were comparable between the two groups. While the incidence of adverse events was not different between the TDM group and the non-TDM group (both 42%; P = .97), the proportion of voriconazole discontinuation due to adverse events was significantly lower in the TDM group than in the non-TDM group (4% vs 17%; P = .02). A complete or partial response was observed in 81% (30 of 37) of patients in the TDM group compared to 57% (20 of 34) in the non-TDM group (P = .04). CONCLUSIONS: Routine TDM of voriconazole may reduce drug discontinuation due to adverse events and improve the treatment response in invasive fungal infections. CLINICAL TRIAL REGISTRATION: NCT00890708.

Efficacy, tolerability, and pharmacokinetics of oxcarbazepine oral loading in patients with epilepsy.

The rapid achievement of effective levels of antiepileptic drugs (AEDs) is required in patients with epilepsy who have a higher risk of seizures, and oral loading of AEDs may be an important consideration in these patients. We performed the present study to investigate the efficacy and tolerability of oral loading of oxcarbazepine in patients with recurrent seizures, or after temporary discontinuation of AEDs for diagnostic or presurgical evaluation of epilepsy. Forty adult patients were studied and oxcarbazepine was administered orally at a single loading dosage of 30 mg/kg. The plasma levels of oxcarbazepine and its active metabolite, 10,11-dihydro-10-hydroxy-carbazepine (monohydroxy derivative, MHD), were measured, and clinical assessment of adverse events was performed at 2, 4, 6, 8, 10, 12, 16, and 24 h after oral loading of oxcarbazepine. Approximately two-thirds of patients reached effective levels of MHD 2 h after receiving the oral loading, and all patients reached effective levels 4 h after oxcarbazepine administration. Most patients maintained therapeutic MHD levels for at least 16 h. Almost half of the patients experienced adverse events, but all were mild to moderate in severity and resolved spontaneously within 24 h. Our study shows that oral loading of oxcarbazepine is an effective and well-tolerated method for rapidly achieving therapeutic levels of MHD in patients with epilepsy, and is a useful option in selected patients with recurrent seizures, or after temporary discontinuation of AEDs.

Pharmacokinetics and pharmacodynamics of oral tolvaptan administered in 15- to 60-mg single doses to healthy Korean men.

Tolvaptan is a selective arginine vasopressin V2-receptor antagonist that is used as an aquaretic agent. This trial investigated the pharmacokinetics and pharmacodynamics of 15- to 60-mg single oral doses of tolvaptan in healthy Korean men. A dose block-randomized, placebo-controlled, double-blind, single ascending dose trial was conducted with 46 subjects receiving tolvaptan (15, 30, or 60 mg) or placebo. To determine pharmacokinetics and pharmacodynamics, blood and urine samples were collected at baseline and up to 48 hours after drug administration. Urine volume and fluid intake were measured for 24 hours starting the day before dosing (day -1) as baseline, and on the day of drug administration (day 1). Tolvaptan showed dose-linear pharmacokinetic characteristics regarding area under the concentration-time curve. Changes from baseline in 24-hour urine volume and 24-hour fluid balance correlated significantly with area under the concentration-time curve from time 0 to the last measurable time. Dose-dependent increases were observed in serum osmolality, serum sodium concentration, and free water clearance in the 4- to 8-hour interval after dosing, and these increases were maintained for at least 24 hours. Single 15- to 60-mg doses of tolvaptan exhibited linear pharmacokinetics and resulted in substantial, dose-dependent aquaresis in healthy Korean men.