The investigation of pyruvate kinase activating drugs is expanding into previously untested diseases as the benefits of increasing glycolytic flux within pyruvate kinase-expressing tissues emerges. Recently, we reported the discovery of allosteric activator tebapivat, an investigational drug currently being studied in lower-risk myelodysplastic syndrome and sickle cell disease patients. This new compound is chemically distinct from the other marketed or investigational pyruvate kinase activators and demonstrated pharmacodynamic effects at low plasma exposures in healthy volunteers. To further distinguish the tebapivat chemotype, this report describes the pharmacokinetic and pharmacodynamic studies used to advance tebapivat to the clinic. Good oral bioavailability and low clearance were observed across animal species, but corrections for in vitro species differences in plasma binding were necessary to predict human clearance from animals. In mouse pharmacodynamic studies, blood biomarkers of pyruvate kinase activation reached near-maximum effect-area-under-the-curve changes at low oral dose (similar to 0.03 mg/kg). Lastly, we observed long-lived blood pharmacodynamics (up to 14 d), non-linear red blood cell partitioning, and the convergence of terminal blood drug concentrations from different doses in mice. We hypothesize these findings are most consistent with target-mediated drug disposition and are a result of the long residence time of tebapivat on its pharmacological target pyruvate kinase in red blood cells, and thus represents a subtle saturable property related to the high potency of tebapivat.
Doxorubicin hydrochloride liposome injection represents a complex nano-drug delivery system with significant clinical advantages, yet its quality evaluation remains challenging. Traditional static release methods often fail to simulate the physiological environment, which leads to poor in vivo predictions. The flow-through cell method provides distinct advantages by simulating hemodynamic characteristics and maintaining stable sink conditions. This study utilizes the flow-through cell method to simulate the release process of doxorubicin hydrochloride liposomes and establishes a Level A in vitro-in vivo correlation (IVIVC) based on the in vivo data of three commercial brands to develop a biorelevant in vitro release method. The in vivo cumulative release fraction is derived from the plasma concentration data of three commercial products using the fractional area (AUC) method for deconvolution, which serves as the target reference for the in vitro release profile. In vitro release experiments are conducted using a phosphate buffer containing 0.3% SDS and 15% artificial plasma as the release medium, which is optimized through single-factor analysis and an L 9 (34) orthogonal experimental design. The experimental setup employs a dialysis membrane with a 300 KDa molecular weight cutoff and a flow rate of 4 mL/min. High-performance liquid chromatography (HPLC) determines the concentration of the released drug to calculate the in vitro cumulative release fraction. A Level A IVIVC model is established between the cumulative in vitro and in vivo release fractions of doxorubicin hydrochloride liposome injection, which is subsequently confirmed through internal validation. The IVIVC model demonstrates robust predictive capability, and the developed in vitro release method exhibits high sensitivity in distinguishing the release characteristics of products from different manufacturers. This study provides a scientific reference for the in vitro-in vivo correlation and quality evaluation of long-acting injections.
In a previous study, retrospective predictions of human serum concentration-time profiles for three therapeutic monoclonal antibodies (mAbs) with linear pharmacokinetics were performed using allometric scaling in common marmosets and achieved favorable predictability. To generalize this method, in the present study, golimumab and ustekinumab, which exhibit linear pharmacokinetics, were repeatedly administered to marmosets. Additionally, the immunogenicity of these mAbs in common marmosets was evaluated. Golimumab and ustekinumab were administered in four repeated doses. Following the initial administration, the scaling exponents of the two mAbs were calculated, and the average scaling exponents of the five mAbs were used for the predictions. Furthermore, serum anti-ustekinumab and anti-golimumab antibodies were evaluated following the repeated-dose administration. Human serum concentration-time curves of golimumab and ustekinumab were predicted using the average scaling exponents of the five mAbs. Although the predictability of the golimumab elimination rate was slightly inferior, ustekinumab showed excellent prediction performance. Low levels of anti-ustekinumab antibodies were detected in the serum when the serum ustekinumab levels were considered to have completely diminished. Furthermore, serum anti-golimumab antibodies were negligible during the experimental period. We identified provisional optimal scaling exponents for predicting human PK and found minimal anti-drug antibody formation. As the cost of acquiring and maintaining cynomolgus monkeys is increasing, pharmacokinetic data of marmosets is expected to encourage the potential use of these small non-human primates as an alternative model.
Glomerular filtration rate (GFR) maturation is critical for drug dosing in neonates and children. Current equations face dual limitations: they are primarily derived from Caucasian populations and fail to account for the fundamental physiological differences between neonates and children. This study aimed to develop Chinese-specific GFR equations and to characterize how the key predictors of GFR differ between these two developmental stages. Creatinine clearance as measured GFR (mGFR) in 58 hospitalized neonates (gestational age range, 30.3-41.0 weeks, postnatal age range, 0 to 26 days, mGFR = 3.08 ± 1.86 mL/min) without renal impairment were enrolled. Moreover, a published database of Chinese children (N = 87, age range, 1 to 18 years, mGFR = 97.0 ± 31.9 mL/min/1.73 m2) was applied. Demographic and renal function markers were included to develop equations using the stepwise regression method in allometric form. The GFR prediction equation of serum cystatin C, blood urea nitrogen and postmenstrual age of Chinese neonates was established. In children, GFR is associated with cystatin C, creatinine, weight and age. In an internal comparison with 16 published equations, our newly developed models showed favorable performance within our cohorts, with correlation (R2 of 0.617 and 0.578) and accuracy (P20 of 46.6% and 70.1%, P50 of 93.1% and 100%), respectively. The equations would provide scientific basis for aiding diagnosis of renal function of Chinese neonates and children, and supporting better precision medicine of drugs mainly excreted by kidney.
Echinacea is a widely used herbal supplement and is frequently co-administered with antiviral drugs, raising concerns regarding potential herb-drug interactions. This study evaluated the effect of repeated Echinacea administration on the pharmacokinetics of favipiravir and atazanavir in rats. Male Sprague Dawley rats were administered Echinacea (250 mg/kg) or vehicle once daily for 10 days, followed by a single oral dose of favipiravir (70 mg/kg) or atazanavir (35 mg/kg). Plasma drug concentrations were quantified using validated LC-MS/MS methods, and pharmacokinetic parameters were determined by noncompartmental analysis. Echinacea co-administration did not significantly alter favipiravir exposure (Cmax: 39,677 ± 5385 vs. 36,364 ± 5379 ng/mL; AUC0-t: 144,457 ± 17,267 vs. 104,840 ± 27,001 ng h/mL) or atazanavir exposure (Cmax: 3274 ± 256 vs. 4004 ± 629 ng/mL; AUC0-t: 8962 ± 1667 vs. 10,645 ± 2949 ng h/mL). No relevant changes were observed in clearance, half-life, or mean residence time for either drug. These findings indicate that repeated Echinacea administration does not result in a pharmacokinetically relevant interaction with favipiravir or atazanavir under the investigated conditions.
