AUC0-24h Values Research Articles

Pharmacokinetic Analysis of an Isoniazid Suspension Among Spanish Children Under 6 Years of Age

Background: Isoniazid (INH) remains a first-line drug for the treatment of tuberculosis (TB) in young children. In 2010, the WHO recommended an increase in the daily dose of INH up to 10 (7–15) mg/kg. Currently, there are no INH suspensions available in Europe. Methods: We aimed to characterize the pharmacokinetics of a licensed INH suspension (10 mg/mL, Pharmascience Inc., Montreal, QC, Canada) in children receiving INH daily at 10 mg/kg in a single-center, open-label, non-randomized, phase IIa clinical trial (EudraCT Number: 2016-002000-31) in Barcelona (Spain). Samples were analyzed using a validated UPLC-UV assay. The N-acetyltransferase 2 gene was examined to determine the acetylation status. A non-compartmental pharmacokinetic analysis was conducted. Results: Twenty-four patients (12 females) were included (primary chemoprophylaxis, n = 12; TB treatment, n = 9; and TB infection preventive treatment, n = 3). The acetylator statuses were homozygous fast (n = 3), heterozygous intermediate (n = 18), and homozygous slow (n = 2; unavailable in one patient). The INH median (IQR) Cmax and AUC0–24h values were 6.1 (4.5–8.2) mg/L and 23.0 (11.2–35.4) h∙mg/L; adult targets (>3 mg/L and 11.6–26.3 h∙mg/L) were not achieved in three and six cases, respectively. Gender, age at assessment (<2 or >2 years), and INH monotherapy (vs. combined TB treatment) had no impact on pharmacokinetic parameters. Significant differences in Cmax (p = 0.030) and AUC0–24h (p = 0.011) values were observed based on acetylator status. Treatment was well tolerated, and no severe adverse events were observed; three patients developed asymptomatic mildly elevated alanine aminotransferase levels. Conclusions: In infants and children receiving a daily INH suspension at 10 mg/kg, no safety concerns were raised, and the target adult levels were reached in the majority of patients.

Systematic Quantitative Analysis of Fetal Dexamethasone Exposure and Fetal Lung Maturation in Pregnant Animals: Model Informed Dexamethasone Precision Dose Study.

Dexamethasone (DEX) was applied in neonatal respiratory distress syndrome treatment of pregnant women. We established a pharmacokinetics (PK)/pharmacodynamics(PD)/end point model of pregnant animals based on published data and then extrapolated to simulate fetal exposure and lung maturation in pregnant women. We first established the PK/PD/end point model for DEX in pregnant sheep. We considered the competitive effect of cortisol (Cort) and DEX binding with glucocorticoid receptor and then used the indirect response model to describe disaturated-phosphatidylcholine (DSPC) dynamics. Based on that, we established a regression relationship between DSPC and fetal lung volume (V40). We then extrapolated the PD/end point model of pregnant sheep to pregnant monkeys by corrected stages of morphologic lung maturation in two species. Finally, we utilized the interspecies extrapolation strategy to simulate fetal exposure (AUC0-48h) and V40 relationship in pregnant women. The current model could well describe the maternal-fetal PK of DEX in pregnant animals. Simulated DEX AUC0-24h values of the umbilical venous to maternal plasma ratio in pregnant sheep and monkeys were 0.31 and 0.27, respectively. The simulated Cort curve and V40 in pregnant sheep closely matched the observed data within a 2-fold range. For pregnant monkeys, model-simulated V40 were well fitted with external verification data, which showed good interspecies extrapolation performance. Finally, we simulated fetal exposure-response relationship in pregnant women, which indicated that the fetal AUC0-48h of DEX should not be less than 300 and 100 ng/mL·hr at GW28 and GW34 to ensure fetal lung maturity. The current model preliminarily provided support for clinical DEX dose optimization.

Design, Optimization, and Evaluation of Chitosan-2-mercaptobenzoic Acid as a Dual-functionalized Thiomer

Aims: This study aimed to develop and evaluate mucoadhesive microspheres for the controlled release of zidovudine using a novel dual-functionalized polymer. Background: Mucoadhesive polymers have recently been widely used to prolong the GI residence time and to modulate the release impact of various mucoadhesive dosage forms. In the present study, a recently synthesized chitosan derivative, chitosan-2-mercapto benzoic acid, was used as a mucoadhesive polymer, which was further developed as a dosage form for improving oral bioavailability of zidovudine drug. Objective: The objective of this study is to evaluate the impact of a novel thiolated derivative, chitosan-2-mercaptobenzoic acid, on the oral bioavailability of the drug zidovudine. Methods: The microspheres were prepared using an emulsification crosslinking method with TPP as the crosslinking agent. Techniques such as FTIR, and DSC were employed to analyze the microspheres, along with drug content, entrapment efficiency, dissolution studies, mucoadhesion, ex vivo permeation, and in vivo evaluations. Results: Results from FTIR spectroscopy and DSC analysis revealed no interaction between the drug and polymers. The release kinetics and characterization assessments indicated a zero-order release profile with anomalous and super case-II transport types. Ex vivo permeation studies on goat intestinal mucosa demonstrated enhanced mucoadhesive properties and permeability with the optimized microspheres fabricated using thiomers compared to conventional oral therapy. Pharmacokinetic investigations showed higher zidovudine plasma levels and Cmax with the administration of microspheres, particularly those composed of thiomers. The AUC0-24h values for thiomer microspheres were significantly greater than controls and chitosan microspheres, indicating improved oral bioavailability potential. Conclusion: In conclusion, zidovudine-loaded thiomer-based mucoadhesive microspheres showed promising results with the ability to enhance the drug's oral bioavailability.

Improving the physicochemical and pharmacokinetic properties of olaparib through cocrystallization strategy

Olaparib (OLA) is the first PARP inhibitor worldwide used for the treatment of ovarian cancer. However, the oral absorption of OLA is extremely limited by its poor solubility. Herein, pharmaceutical cocrystallization strategy was employed to optimize the physicochemical and pharmacokinetic properties. Four cocrystals of OLA with oxalic acid (OLA-OA), malonic acid (OLA-MA), fumaric acid (OLA-FA) and maleic acid (OLA-MLA) were successfully discovered and characterized. Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy confirmed the formation of cocrystals rather than salts, and the possible hydrogen bonding patterns were analyzed through molecular surface electrostatic potential calculations. The in vitro and in vivo evaluations indicate that all of the cocrystals demonstrate significantly improved dissolution performance, oral absorption and tabletability compared to pure OLA. Among them, OLA-FA exhibit sufficient stability and the most increased Cmax and AUC0-24h values that were 11.6 and 6.1 times of free OLA, respectively, which has great potential to be developed into the improved solid preparations of OLA.

Improved Pharmacokinetic Feasibilities of Mirabegron-1,2-Ethanedisulfonic Acid, Mirabegron-1,5-Naphthalenedisulfonic Acid, and Mirabegron-L-Pyroglutamic Acid as Co-Amorphous Dispersions in Rats and Mice.

Mirabegron (MBR) is a β3-adrenoceptor agonist used for treating overactive bladder syndrome. Due to its poor solubility and low bioavailability (F), the development of novel MBR formulations has garnered increasing attention. Recently, co-amorphous dispersions of MBR, such as MBR-1,2-ethanedisulfonic acid (MBR-EFA), MBR-1,5-naphthalenedisulfonic acid (MBR-NDA), and MBR-L-pyroglutamic acid (MBR-PG), have been developed, showing improved solubility and thermodynamic stability. Nevertheless, the pharmacokinetic feasibility of these co-amorphous dispersions has not been evaluated. Therefore, this study aimed to characterize the pharmacokinetic profiles of MBR-EFA, MBR-NDA, and MBR-PG in rats and mice. Our results exhibited that relative F24h and AUC0-24h values of MBR in MBR-EFA, MBR-NDA, and MBR-PG rats were increased by 143-195% compared with the MBR rats. The absolute F24h, relative F24h, and AUC0-24h values of MBR in MBR-EFA and MBR-NDA mice were enhanced by 178-234% compared with the MBR mice. In tissue distribution, MBR was extensively distributed in the gastrointestinal tract, liver, kidneys, lung, and heart of mice. Notably, MBR distribution in the liver, kidneys, and lung was considerably high in MBR-EFA, MBR-NDA, or MBR-PG mice compared with MBR mice. These findings highlight the potential of these co-amorphous dispersions to enhance oral F of MBR.

Toxicokinetics of recombinant human fibroblast growth factor 21 for injection in cynomolgus monkey for 3months.

Introduction: Recombinant human fibroblast growth factor 21 (FGF-21) is a potential therapeutic agent for multiple metabolic diseases. However, little is known about the toxicokinetic characteristics of FGF-21. Methods: In the present study, we investigated the toxicokinetics of FGF-21 delivered via subcutaneous injection in vivo. Twenty cynomolgus monkeys were injected subcutaneously with different doses of FGF-21 for 86days. Serum samples were collected at eight different time points (0, 0.5, 1.5, 3, 5, 8, 12, and 24h) on day 1, 37 and 86 for toxicokinetic analysis. The serum concentrations of FGF-21 were measured using a double sandwich Enzyme-linked immunosorbent assay. Blood samples were collected on day 0, 30, 65, and 87 for blood and blood biochemical tests. Necropsy and pathological analysis were performed on d87 and d116 (after recovery for 29days). Results: The average AUC(0-24h) values of low-dose FGF-21 on d1, d37, and d86 were 5253, 25268, and 60445μgh/L, and the average AUC(0-24h) values of high-dose FGF-21 on d1, d37, and d86 were 19964, 78999, and 1952821μgh/L, respectively. Analysis of the blood and blood biochemical indexes showed that prothrombin time and AST content in the high-dose FGF-21 group increased. However, no significant changes in other blood and blood biochemical indexes were observed. The anatomical and pathological results showed that continuous subcutaneous injection of FGF-21 for 86 days did not affect organ weight, the organ coefficient, and histopathology in cynomolgus monkeys. Discussion: Our results have guiding significance for the preclinical research and clinical use of FGF-21.

Lutein–stachyose (LS) amphiphilic oligosaccharide derivatives improve the oral bioavailability of lutein

A new amphiphilic oligosaccharide derivative, based on lutein modification onto the OH position of stachyose with facile and mild esterification, was prepared and used to improve the oral bioavailability of lutein. The structures of lutein–stachyose derivative (LS) were confirmed by Fourier transform infrared spectroscopy and hydrogen-1 nuclear magnetic resonance, indicating that one stachyose is connected to one lutein through succinic acid. The critical micelle concentration of LS was approximately 6.86 ± 0.24 mg/mL, corresponding to the free lutein concentration of approximately 2.96 mg/mL. LS has better digestive stability and free radical scavenging ability, and it could inhibit the degradation of lutein in the gastrointestinal tract. Importantly, LS is nontoxic to cells and zebrafish embryos. In terms of oral bioavailability in rats, the AUC0-12h values of LS were 2.26 times higher than those of free lutein. Therefore, stachyose modification is a promising strategy for improving the oral bioavailability of fat-soluble lutein.

Adequacy of the 10 mg/kg Daily Dose of Antituberculosis Drug Isoniazid in Infants under 6 Months of Age.

In 2010, the WHO recommended an increase in the daily doses of first-line anti-tuberculosis medicines in children. We aim to characterize the pharmacokinetics of the once-daily isoniazid (INH) dose at 10 mg/kg of body weight in infants <6 months of age. We performed a multicenter pharmacokinetic study in Spain. The N-acetyltransferase 2 gene was analyzed to determine the acetylation status. Samples were analyzed using a validated UPLC-UV assay. A non-compartmental pharmacokinetic analysis was performed. Twenty-three pharmacokinetic profiles were performed in 20 infants (8 females) at a median (IQR) age of 19.0 (12.6-23.3) weeks. The acetylator statuses were homozygous fast (n = 1), heterozygous intermediate (n = 12), and homozygous slow (n = 7). INH median (IQR) Cmax and AUC0-24h values were 4.8 (3.7-6.7) mg/L and 23.5 (13.4-36.7) h*mg/L and the adult targets (>3 mg/L and 11.6-26.3 h*mg/L) were not reached in three and five cases, respectively. The age at assessment or acetylator status had no impact on Cmax values, but a larger INH AUC0-24h (p = 0.025) and trends towards a longer half-life (p = 0.055) and slower clearance (p = 0.070) were observed in homozygous slow acetylators. Treatment was well tolerated; mildly elevated alanine aminotransferase levels were observed in three cases. In our series of young infants receiving isoniazid, no major safety concerns were raised, and the target adult levels were reached in most patients.

Comparison of the effects of peficitinib and tofacitinib in the adjuvant-induced arthritis rat model

We investigated and compared the pharmacologic properties of two Janus kinase (JAK) inhibitors, peficitinib and tofacitinib, in an adjuvant-induced arthritis rat model. Repeated administration of peficitinib (3 − 30 mg/kg) or tofacitinib (1 − 10 mg/kg) exhibited a dose-related and significant attenuation of arthritis score, paw swelling, pain threshold, grip strength and histopathologic injuries in the model; peficitinib 10 mg/kg and tofacitinib 3 mg/kg demonstrated comparable efficacy. Equivalent Cmax and AUC0–12h values were observed with peficitinib 10 mg/kg and tofacitinib 3 mg/kg, suggesting that the two drugs may demonstrate comparable efficacy on arthritis-associated symptoms at comparable plasma concentration levels. However, peficitinib 10 mg/kg had greater efficacy than tofacitinib 3 mg/kg on some inflammation- and bone destruction-associated parameters in the paw fluid, including the production of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), receptor activator of nuclear factor kappa-B ligand, and matrix metalloproteinase-3, which are associated with arthritis exacerbation. Peficitinib 10 mg/kg also showed significantly greater inhibitory effects than tofacitinib 3 mg/kg on loss of bone mineral density and synovial thickening score, which might be a result of the VEGF and PDGF receptor kinase inhibitory effects of peficitinib, in addition to JAK inhibition. In conclusion, both tofacitinib and peficitinib potently improved arthritis and associated symptoms in adjuvant-induced arthritis rats; moreover, owing to possible differences in the mechanism of action of the two drugs, peficitinib may have exerted its effects through JAK inhibition and additional unique off-target properties.

Simulation of febuxostat pharmacokinetics in healthy subjects and patients with impaired kidney function using physiologically based pharmacokinetic modeling.

Febuxostat is recommended by the American College of Rheumatology Gout Management Guidelines as a first-line therapy for lowering the level of urate in patients with gout. At present, this drug is being prescribed mainly based on the clinical experience of doctors. The potential effects of clinical and demographic variables on the bioavailability and therapeutic effectiveness of febuxostat are not being considered. In this study a physiologically based pharmacokinetic (PBPK) model of febuxostat was developed, thereby providing a theoretical basis for the individualized dosing of this drug in gout patients. The plasma concentration-time profiles corresponding to healthy subjects and gout patients with normal kidney function were simulated and validated; then, the model was used to predict the pharmacokinetic (PK) data of the drug in gout patients suffering from varying degrees of impaired kidney function. The error values (the predicted value/observed value) were used to validate the simulated PK parameters predicted by the PBPK model, including the area under the plasma concentration-time curve, the maximum plasma concentration, and time to maximum plasma concentration. Considering that to all error fold changes were smaller than 2, the PBPK model was. In subjects suffering from mild kidney impairment, moderate kidney impairment, severe kidney impairment, and endstage kidney disease (ESRD), the predicted AUC0-24h values increased by 1.62, 1.74, 2.27, and 2.65-fold, respectively, compared to gout patients with normal kidney function. Overall, the results showed that the PBPK model constructed in this study predict the pharmacokinetic changes in gout patients suffering from varying degrees of impaired kidney function.

Impact of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of lenvatinib in patients with hepatocellular carcinoma

This prospective study examined the impact of genetic polymorphisms on the pharmacokinetics and clinical efficacy and safety of lenvatinib, a substrate of ATP-binding transporters, in a cohort of 48 Japanese patients with hepatocellular carcinoma (HCC). Pharmacokinetic studies were performed at the start of lenvatinib therapy (day 1) and on day 15. The coefficients of variation in AUC0–24h of lenvatinib on days 1 and 15 were 44.0% and 52.4%, respectively. Although the ABCB1 3435C > A, 1236C > T, and 2677G>T/A polymorphisms did not influence pharmacokinetic parameters, the AUC0–24h values on days 1 and 15 of the ABCG2 C/A or A/A group were approximately 1.1-fold and 1.4-fold that in the ABCG2 C/C group (P = 0.164 and 0.024). There were no significant differences in AUC0–24h on days 1 and 15 between the responders (complete or partial response) and non-responders (stable or progressive disease). The AUC0–24h on day 15 in those developing anorexia of any grade was significantly higher than that without such development (P = 0.017). In multivariate analysis, ABCG2 421C > A C/A or A/A was significantly associated with the development of anorexia (odds ratio 9.009, P = 0.009). ABCG2 421C > A polymorphism could affect exposure to lenvatinib and the development of anorexia.

Dexamethasone Pharmacokinetics Following Standard and Short Dosing Schedules in Patients on the UKALL2011 Trial

Dexamethasone (Dex) is a key component of ALL therapy, with glucocorticoid sensitivity strongly linked to prognosis. However, it also contributes to both short and long term toxicities. The UKALL 2011 trial (ISRCTN64515327) investigated a shorter schedule of Dex as part of randomisation 1 (R1) (10mg/m2 x 14 days vs 6mg/m2 x 28 days), in an attempt to bring about a more rapid cytoreduction whilst limiting toxicities associated with long term steroid exposure. There are limited data regarding Dex pharmacokinetics, however large variability has been reported in children being treated for ALL (Yang et al. 2008).To investigate Dex pharmacokinetics in the context of the UKALL2011 randomised dex dosing and scheduling, blood samples were collected up to 8h post oral administration of Dex on one of the first three days, and one of the last three days of induction chemotherapy. Plasma Dex levels were analysed using a fully validated tandem reverse phase LC-MS method, and non-compartmental pharmacokinetic analysis was performed using Pheonix WinNonlin.Pharmacokinetic parameters from day one sampling are shown in the table below. Exposure, as defined by AUC0-12h, and Cmax were significantly higher on the short arm (n=72) compared to the standard arm (n=53) (p=<0.0001 for both). However, there was substantial overlap between the two arms, with a number of patients on the standard arm exhibiting higher exposures than those on short therapy, despite having a longer duration of treatment, and vice versa. This variation is displayed in the greater than 20-fold variation in AUC0-12h values observed on the two arms (short: 69.1-1,606; standard: 38.3-1,009 hr*ng/mL). When AUC values were extrapolated to the duration of Dex therapy on short and standard arms, patients on the standard arm had a significantly larger overall exposure compared to those on the short arm (short: 16,318 (14,177-19,568) vs. standard: 22,570 (18,012-25,550) hr*ng/mL, median (95% CI) p=0.01).Early response data would indicate a trend towards a higher Dex exposure (AUC) in patients with a day 8 bone marrow blast count <5% versus those patients with a day 8 blast count >5 % (595.3 (458.5-843.7) vs 441.7 (387.5-552.1) hr*ng/mL, median (95% CI) p=0.0006). However, there was no statistical difference between the two randomisation arms in terms of day 8 blast count (p=0.2). Pharmacokinetic profiles also differed between the two days of treatment, with AUC0-12h being significantly higher at the end of induction chemotherapy (n=52, study day 1: 562.5 (435.7-756.5); study day 2:794.5 (648.7-1041) hr*ng/mL, (median (95% CI) p=0.0003).The UKALL 2011 R1 found no statistical difference in terms of steroid related toxicity or MRD response between short and standard Dex dosing. The data generated from patients recruited to the pharmacology sub-study shows considerable variation in Dex pharmacokinetics and suggest that pharmacokinetic variability may be a more important factor than variation in dosing regimen on the two arms of the randomisation. Furthermore, a significantly higher cumulative exposure of patients on the standard arm suggests that in a drug treatment with markedly variable pharmacokinetics, duration of therapy may be more important in terms of the likely impact on clinical response and toxicity. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

In vitro and in vivo evaluation of a sustained-release once-a-day formulation of the novel antihypertensive drug MT-1207

Hypertension is one of the most common chronic cardiovascular disorders. Sustained-release formulations are developed to maintain drug therapeutic levels throughout the treatment of hypertension, to promote patient compliance and improve patient outcomes. We have developed and tested in in vivo trials a once-a-day tablet formulation for the novel antihypertensive drug MT-1207. The tablets based upon a hydrophilic polymer matrix underwent post-compression parameter and physicochemical characterisations, along with in vitro drug release testing. The most promising formulation containing 31% w/w HPMC K15M gave a 24-hour release of MT-1207 with an almost constant release rate up to 20 hours. Follow in in vivo studies were carried out in Beagle dogs for the optimised sustained-release tablets in comparison to immediate-release tablets. The results showed that a sustained release of MT-1207 from the new formulation was achieved with a drug t1/2 2–2.5 times longer than the immediate-release tablets. Moreover, the AUC0-24h values of both sustained- and immediate-release tablets were identical at the same dose of 30 mg, indicating that the same amount of drug was absorbed in each case. For treatments based upon MT-1207, this development is significant for future commercial exploitation via scale-up and further trials, and for improved patient outcomes.

Detection of Weak Organic Anion–Transporting Polypeptide 1B Inhibition by Probenecid with Plasma-Based Coproporphyrin in Humans

Probenecid (PROB) is a clinical probe inhibitor of renal organic anion transporter (OAT) 1 and OAT3 that inhibits in vitro activity of hepatic drug transporters OATP1B1 and OATP1B3. It was hypothesized that PROB could potentially affect the disposition of OATP1B drug substrates. The plasma levels of the OATP1B endogenous biomarker candidates, including coproporphyrin I (CPI), CPIII, hexadecanedioate (HDA), and tetradecanedioate (TDA), were examined in 14 healthy subjects treated with PROB. After oral administration with 1000 mg PROB alone and in combination with furosemide (FSM), AUC (0-24 h) values were 1.39 ± 0.21-fold and 1.57 ± 0.41-fold higher than predose levels for CPI and 1.34 ± 0.16-fold and 1.45 ± 0.57-fold higher for CPIII. Despite increased systemic exposures, no decreases in CPI and CPIII renal clearance were observed (0.97 ± 0.38-fold and 1.16 ± 0.51-fold for CPI, and 1.34 ± 0.53-fold and 1.50 ± 0.69-fold for CPIII, respectively). These results suggest that the increase of CP systemic exposure is caused by OATP1B inhibition. Consistent with this hypothesis, PROB inhibited OATP1B1- and OATP1B3-mediated transport of CPI in a concentration-dependent manner, with IC50 values of 167 ± 42.0 and 76.0 ± 17.2 µM, respectively, in transporter-overexpressing human embryonic kidney cell assay. The inhibition potential was further confirmed by CPI and CPIII hepatocyte uptake experiments. In contrast, administration of PROB alone did not change AUC (0-24 h) of HDA and TDA relative to prestudy levels, although the administration of PROB in combination with FSM increased HDA and TDA levels compared with FSM alone (1.02 ± 0.18-fold and 0.90 ± 0.20-fold vs. 1.71 ± 0.43-fold and 1.62 ± 0.40-fold). Taken together, these findings indicate that PROB displays weak OATP1B inhibitory effects in vivo and that coproporphyrin is a sensitive endogenous probe of OATP1B inhibition. This study provides an explanation for the heretofore unknown mechanism responsible for PROB's interaction with other xenobiotics. SIGNIFICANCE STATEMENT: This study suggested that PROB is a weak clinical inhibitor of OATP1B based on the totality of evidence from the clinical interaction between PROB and CP and the in vitro inhibitory effect of PROB on OATP1B-mediated CP uptake. It demonstrates a new methodology of utilizing endogenous biomarkers to evaluate complex drug-drug interaction, providing explanation for the heretofore unknown mechanism responsible for PROB's inhibition. It provides evidence to strengthen the claim that CP is a sensitive circulating endogenous biomarker of OATP1B inhibition.

SUN-608 Juvenile Toxicity Study of Livoletide: A Peptide Analogue of Unacylated Ghrelin for the Treatment of Hyperphagia in Prader-Willi Syndrome

Background: Prader-Willi syndrome (PWS) is a rare endocrine disorder characterized by hyperphagia and abnormal food-related behaviors that contribute to severe morbidity, early mortality, and significant burdens for patients and caregivers. Dysregulation of acylated ghrelin (AG) and unacylated ghrelin (UAG) in people with PWS and hyperphagia has led to the hypothesis that replacing the relative deficit of UAG observed in this population will reduce hyperphagia. Livoletide is a cyclic, 8 amino acid analogue of UAG being developed as a potential treatment for hyperphagia and food-related behaviors associated with PWS. In a previous Phase 2a study (n=47) in people with PWS, livoletide improved food-related behaviors and hyperphagia scores relative to placebo. An extensive nonclinical safety program to support clinical development of livoletide has been conducted. Here we report the results of study of livoletide in juvenile rats. Methods: Male and female juvenile Wistar rats were administered livoletide (10, 25, or 75 mg/kg/day, subcutaneous) once daily from the age of weaning (postnatal day 21) until 12 weeks of age (n=32/sex/group). Subgroups were sacrificed at the end of the dosing period or after a recovery period. Toxicity was assessed based on local tolerance, clinical observations, body weights, food consumption, tibia length, bone densitometry, behavioral tests, IGF1 (insulin-like growth factor-1), LH (luteinizing hormone), and other endpoints. Macroscopic (necropsy), microscopic/histopathological, and caesarean examinations were also performed. Toxicokinetic (TK) evaluations were performed at various time-points after dosing to assess exposure. Results: Livoletide was not associated with treatment-related clinical signs or any relevant changes in hematological, coagulation, clinical chemistry parameters or urine analysis. Body weight and food consumption were unaffected. Livoletide did not affect systemic concentrations of IGF-1 or LH. No adverse effects of livoletide on bone growth, mating performance, or fertility were observed. Pups delivered by caesarian section did not exhibit abnormalities. Results were consistent with a lack of effect of livoletide on growth hormone signaling. Histological changes were limited to minimal local reversible reactions at injection sites that were non-adverse and observed at low incidence and severity. Conclusions: Livoletide was well-tolerated and not associated with evidence of overt systemic toxicity. The no observed adverse effect level (NOAEL) of 75 mg/kg/day was associated with Cmax and AUC0-24h values of 72.6/83.2 μg/mL and 169/144 μg.h/mL (males/females), respectively. These exposures are >100-fold above the anticipated clinical exposures in the Phase 2b/3 ZEPHYR study, which is enrolling people ages 4 to 65 with PWS.

Impact of dose and duration of therapy on dexamethasone pharmacokinetics in childhood acute lymphoblastic leukaemia—a report from the UKALL 2011 trial

IntroductionThe use of dexamethasone in acute lymphoblastic leukaemia therapy contributes to short- and long-term toxicities. The UKALL 2011 randomised trial investigated whether a more intense dexamethasone dose (10 mg/m2/d x 14d, short vs 6 mg/m2/d x 28d, standard) would lead to a more rapid cytoreduction and reduced adverse effects associated with longer durations of steroids in induction. The impact of dose and duration on dexamethasone pharmacokinetics was investigated. MethodsBlood samples were obtained on one of the first three and last three days of induction dexamethasone dosing at time points up to 8 h after oral administration. Plasma dexamethasone levels were quantified in 1084 plasma samples obtained from 174 children and a population pharmacokinetic model developed. ResultsDrug exposure varied significantly between patients, with a >12-fold variation in AUC0–12h values and a marked overlap in dexamethasone exposures between dose levels. Intuitively, AUC0–12h was significantly higher with short dosing (10 mg/m2/d), but cumulative exposure was significantly higher with standard dosing over 28 days, after a higher cumulative dose. Concomitant rasburicase administration was associated with a 60% higher dexamethasone clearance. Day 8 bone marrow response was comparable between dosing arms, but those with <5% blast count exhibited a greater mean dexamethasone exposure than those with >5%. No statistical differences were observed between arms in terms of steroid-related toxicity or minimal residual disease at the end of induction. ConclusionThe potential significance of dexamethasone AUC0–12h on early response and higher cumulative exposure on the standard arm suggest that duration of therapy and exposure may be more important factors than absolute dose from a clinical pharmacology perspective.

Pharmacokinetics of mycophenolate mofetil in juvenile patients with autoimmune diseases

Objectives: This study aimed to determine the association between the dosage and pharmacokinetics of mycophenolate mofetil (MMF) in juvenile patients with autoimmune diseases.Methods: Totally, 29 patients were administered oral MMF. The blood concentrations of mycophenolate acid (MPA) at seven points, the area under the time–concentration curve (MPA–AUC0–12h), the peak concentration (Cmax), and the time to peak concentration (Tmax) were measured. To obtain a dose-normalized MPA–AUC0–12h value, the actual measured MPA–AUC0–12h value was divided by the dose value of the morning administration corrected for body weight (BW) or body surface area (BSA). The patients were classified into three age groups (group 1, ≤10 years; group 2, >10–≤15 years; and group 3, >15 years), and pharmacokinetic parameters were compared among the groups.Results: In total, we obtained 37 measurements. The actual measured MPA–AUC0–12h values and the MPA–AUC0–12h values corrected for dose per BW and Tmax were lower in young patients. The MPA–AUC0–12h values corrected for dose per BSA and Cmax were comparable among all the groups.Conclusion: In patients with juvenile autoimmune diseases, determining MMF administration dosage according to BSA may facilitate MPA–AUC0–12h value prediction.

Strategy for the Prediction of Steady-State Exposure of Digoxin to Determine Drug–Drug Interaction Potential of Digoxin With Other Drugs in Digitalization Therapy

Digoxin, a narrow therapeutic index drug, is widely used in congestive heart failure. However, the digitalization therapy involves dose titration and can exhibit drug-drug interaction. Ctrough versus area under the plasma concentration versus time curve in a dosing interval of 24 hours (AUC0-24h) and Cmax versus AUC0-24h for digoxin were established by linear regression. The predictions of digoxin AUC0-24h values were performed using published Ctrough or Cmax with appropriate regression lines. The fold difference, defined as the quotient of the observed/predicted AUC0-24h values, was evaluated. The mean square error and root mean square error, correlation coefficient (r), and goodness of the fold prediction were used to evaluate the models. Both Ctrough versus AUC0-24h (r = 0.9215) and Cmax versus AUC0-24h models for digoxin (r = 0.7781) showed strong correlations. Approximately 93.8% of the predicted digoxin AUC0-24h values were within 0.76-fold to 1.25-fold difference for Ctrough model. In sharp contrast, the Cmax model showed larger variability with only 51.6% of AUC0-24h predictions within 0.76-1.25-fold difference. The r value for observed versus predicted AUC0-24h for Ctrough (r = 0.9551; n = 177; P < 0.001) was superior to the Cmax (r = 0.6134; n = 275; P < 0.001) model. The mean square error and root mean square error (%) for the Ctrough model were 11.95% and 16.2% as compared to 67.17% and 42.3% obtained for the Cmax model. Simple linear regression models for Ctrough/Cmax versus AUC0-24h were derived for digoxin. On the basis of statistical evaluation, Ctrough was superior to Cmax model for the prediction of digoxin AUC0-24h and can be potentially used in a prospective setting for predicting drug-drug interaction or lack of it.

Pharmacokinetic Comparison of Two Mycophenolate Mofetil Formulations in Kidney Transplant Recipients

The aim of this study was to investigate and compare the pharmacokinetic (PK) characteristics of mycophenolate mofetil (MMF) capsule and MMF dispersible tablet by detecting the active metabolite of mycophenolic acid (MPA) in Chinese kidney transplant recipients. In the prospective, randomized, open-label study, the renal transplant patients were given a multiple dose of either the MMF capsule or MMF dispersible tablet combination with tacrolimus (Tac). For each patient, 11 serial blood samples were collected over 12 hours (h). Parameters including predose concentration (C0), postdose minimum and maximum concentration (Cmin and Cmax), time to Cmax (Tmax), total body clearance (CL), and area under the concentration-time curve for the 12-hour exposure (AUC0-12h) were determined. Patient interviews were conducted to assess the occurrence of adverse events. Baseline characteristics were comparable between both groups. The C0, Cmin, Cmax, Tmax, CL, and AUC0-12h values were not significantly different after multiple doses of MMF capsule or MMF dispersible tablet (P > 0.05). The median values of AUC0-12h were 43.98 and 41.95 mcg·h/mL for MMF capsule and MMF dispersible tablet, respectively. Interindividual variability in Cmax, Cmin, and C0 were considerable in both groups. No serious adverse events were reported by patients or found on analysis of laboratory tests. PK parameters of the 2 MPA drugs were comparable in early renal transplant patients in this study. The 2 formulations were well tolerated in Chinese kidney transplant patients.

Further Studies to Support the Use of Coproporphyrin I and III as Novel Clinical Biomarkers for Evaluating the Potential for Organic Anion Transporting Polypeptide 1B1 and OATP1B3 Inhibition.

In a recent study, limited to South Asian Indian subjects (n = 12), coproporphyrin (CP) I and CPIII demonstrated properties appropriate for an organic anion-transporting polypeptide (OATP) 1B endogenous probe. The current studies were conducted in healthy volunteers of mixed ethnicities, including black, white, and Hispanic subjects, to better understand the utility of these biomarkers in broader populations. After oral administration with 600 mg rifampin, AUC(0-24h) values were 2.8-, 3.7-, and 3.6-fold higher than predose levels for CPI and 2.6-, 3.1-, and 2.4-fold higher for CPIII, for the three populations, respectively. These changes in response to rifampin were consistent with previous results. The sensitivity toward OATP1B inhibition was also investigated by evaluating changes of plasma CP levels in the presence of diltiazem and itraconazole [administered as part of an unrelated drug-drug interaction (DDI) investigation], two compounds that were predicted to have minimal inhibitory effect on OATP1B. Administration of diltiazem and itraconazole did not increase plasma CPI and CPIII concentrations relative to prestudy levels, in agreement with predictions from in vitro parameters. Additionally, the basal CP concentrations in subjects with SLCO1B1 c.521TT genotype were comparable to those with SLCO1B1 c.521TC genotype, similar to studies with probe substrates. However, subjects with SLCO1B1 c.388AG and c.388GG genotypes (i.e., increased OATP1B1 transport activity for certain substrates) had lower concentrations of CPI than those with SLCO1B1 c.388AA. Collectively, these findings provide further evidence supporting the translational value of CPI and CPIII as suitable endogenous clinical probes to gauge OATP1B activity and potential for OATP1B-mediated DDIs.