Hemoglobin concentration (Hb) in the perioperative setting should be interpreted in the context of the variables and processes that may affect it to differentiate the dilution effects caused by ...changes in intravascular volume. However, it is unclear what variables and processes affect Hb. Here, we modeled the perioperative variations in Hb to identify the variables and processes that govern Hb and to describe their effects.
We first constructed a mechanistic framework based on the main variables and processes related to the perioperative Hb variations. We then prospectively studied patients undergoing laparoscopic surgery, divided into 2 consecutive cohorts for the development and validation of the model. The study protocol consisted of serial measurements of Hb along with recordings of hemoglobin mass loss, blood volume loss, fluid infusion, urine volume, and inflammatory biomarkers measurements, up to 96 hours postoperatively. Mathematical fitting was performed using nonlinear mixed-effects. Additionally, we performed simulations to explore the effects of blood loss and fluid therapy protocols on Hb.
We studied 154 patients: 118 enrolled in the development group and 36 in the validation group. We characterized the perioperative course of Hb using a mass balance model that accounted for hemoglobin losses during surgery, and a 2-compartment model that estimated fluid kinetics and intravascular volume changes. During model development, we found that urinary fluid elimination represented only 24% of the total fluid elimination, and that total fluid elimination was inhibited after surgery in a time-dependent manner and influenced by age. Also, covariate evaluation showed a significant association between the type of surgery and proportion of fluid eliminated via urine. In contrast, neither the type of infused solution, blood volume loss nor inflammatory biomarkers were found to correlate with model parameters. In the validation analysis, the model demonstrated a considerable predictive capacity, with 95% of the predicted Hb within -4.4 and +5.5 g/L. Simulations demonstrated that hemoglobin mass loss determined most of the postoperative changes in Hb, while intravascular volume changes due to fluid infusion, distribution, and elimination induced smaller but clinically relevant variations. Simulated patients receiving standard fluid therapy protocols exhibited a hemodilution effect that resulted in a Hb decrease between 7 and 15 g/L at the end of surgery, and which was responsible for the lowest Hb value during the perioperative period.
Our model provides a mechanistic and quantitative understanding of the causes underlying the perioperative Hb variations.
Highlights • The ability of rodent seizure models to predict antiepileptic efficacy is analysed. • Articles describing PTZ and MES models in literature were included. • Efficacious human ...antiepileptic doses were compared to PTZ and MES ED50 doses. • Exposures at human antiepileptic doses were similar to rodent model doses. • PTZ and MES models are useful in anti-epileptic drug discovery and development.
ABSTRACT
Purpose
Flibanserin is being developed for treating hypoactive sexual desire disorder in women; the main side effect is sedation. The analysis objective was to relate flibanserin plasma ...concentrations with acute sedative effects using a population pharmacokinetic/pharmacodynamic (PK/PD) model.
Methods
The population model was developed with NONMEM based on data from 24 healthy volunteers. “Drowsiness” was serially assessed by a Visual Analogue Scale (VAS) on a baseline day and after morning oral administration of 100 mg flibanserin together with PK sampling.
Results
PK was best described by a three-compartment disposition model and transit compartments accounting for the lag time in absorption. VAS “drowsiness” baseline profiles were modeled using linear splines with three breakpoints located at clock times at first and last observation, and at the median of the observation time across subjects. The drug effect followed a sigmoidal E
MAX
model using predicted effect site concentrations (C
e
). The VAS
vs
. C
e
relationship was very steep and effect site and plasma concentration-time profiles were very similar thus suggesting little delay between the occurrence of maximum flibanserin plasma concentrations and drowsiness.
Conclusions
At effect site concentrations lower than ∼200 ng/mL that are reached approximately 4 h after administration, flibanserin shows hardly any effect on the VAS “drowsiness” scale.
Advanced melanoma remains a disease with poor prognosis. Several serologic markers have been investigated to help monitoring and prognostication, but to date only lactate dehydrogenase (LDH) has been ...validated as a standard prognostic factor biomarker for this disease by the American Joint Committee on Cancer. In this work, we built a semi-mechanistic model to explore the relationship between the time course of several circulating biomarkers and overall or progression free survival in advanced melanoma patients treated with adjuvant high-dose interferon-Formula: see text. Additionally, due to the adverse interferon tolerability, a semi-mechanistic model describing the side effects of the treatment in the absolute neutrophil counts is proposed in order to simultaneously analyze the benefits and toxic effects of this treatment. The results of our analysis suggest that the relative change from baseline of LDH was the most significant predictor of the overall survival of the patients. Unfortunately, there was no significant difference in the proportion of patients with elevated serum biomarkers between the patients who recurred and those who remained free of disease. Still, we believe that the modelling framework presented in this work of circulating biomarkers and adverse effects could constitute an additional strategy for disease monitoring in advance melanoma patients.
Immune checkpoint inhibitors, administered as single agents, have demonstrated clinical efficacy. However, when treating cold tumors, different combination strategies are needed. This work aims to ...develop a semi-mechanistic model describing the antitumor efficacy of immunotherapy combinations in cold tumors. Tumor size of mice treated with TC-1/A9 non-inflamed tumors and the drug effects of an antigen, a toll-like receptor-3 agonist (PIC), and an immune checkpoint inhibitor (anti-programmed cell death 1 antibody) were modeled using Monolix and following a middle-out strategy. Tumor growth was best characterized by an exponential model with an estimated initial tumor size of 19.5 mm3 and a doubling time of 3.6 days. In the treatment groups, contrary to the lack of response observed in monotherapy, combinations including the antigen were able to induce an antitumor response. The final model successfully captured the 23% increase in the probability of cure from bi-therapy to triple-therapy. Moreover, our work supports that CD8+ T lymphocytes and resistance mechanisms are strongly related to the clinical outcome. The activation of antigen-presenting cells might be needed to achieve an antitumor response in reduced immunogenic tumors when combined with other immunotherapies. These models can be used as a platform to evaluate different immuno-oncology combinations in preclinical and clinical scenarios.
A semi-physiological two compartment pharmacokinetic model with two active metabolites (primary (PM) and secondary metabolites (SM)) with saturable and non-saturable pre-systemic efflux transporter, ...intestinal and hepatic metabolism has been developed. The aim of this work is to explore in several scenarios which analyte (parent drug or any of the metabolites) is the most sensitive to changes in drug product performance (i.e. differences in in vivo dissolution) and to make recommendations based on the simulations outcome. A total of 128 scenarios (2 Biopharmaceutics Classification System (BCS) drug types, 2 levels of KM Pgp, in 4 metabolic scenarios at 2 dose levels in 4 quality levels of the drug product) were simulated for BCS class II and IV drugs. Monte Carlo simulations of all bioequivalence studies were performed in NONMEM 7.3. Results showed the parent drug (PD) was the most sensitive analyte for bioequivalence trials in all the studied scenarios. PM and SM revealed less or the same sensitivity to detect differences in pharmaceutical quality as the PD. Another relevant result is that mean point estimate of Cmax and AUC methodology from Monte Carlo simulations allows to select more accurately the most sensitive analyte compared to the criterion on the percentage of failed or successful BE studies, even for metabolites which frequently show greater variability than PD.
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Volasertib, a potent and selective polo-like kinase inhibitor, has shown to increase response rates and improve survival with a clinically manageable safety profile, administered alone and in ...combination with cytarabine in patients with acute myeloid leukaemia.
The objectives of this analysis were to describe the pharmacokinetics of volasertib and cytarabine, administered as single agents or in combination.
Three thousand, six hundred and six plasma volasertib concentrations from 501 patients receiving either volasertib alone, or in combination with cytarabine, and 826 plasma cytarabine concentrations from 650 patients receiving cytarabine as multiple subcutaneous injections per cycle either alone, or in combination with volasertib, were analysed using NONMEM Version 7.3. Covariates evaluated included demographic and disease-related parameters.
The pharmacokinetics of volasertib were found to be dose independent from 150 to 550 mg. Body surface area and ethnicity showed significant effects in all the patients. This is reflected as an increase in drug exposure for Japanese patients, although this finding has to be interpreted with caution because only 7% of patients were part of that population group. Volasertib showed low-to-mild inter-individual variability in total clearance. For the case of cytarabine, its pharmacokinetics was affected by body surface area. Finally, volasertib and cytarabine did not influence the pharmacokinetic characteristics of each other.
The pharmacokinetics of volasertib in patients with acute myeloid leukaemia alone or in combination with cytarabine is predictable and associated with low-to-mild patient variability with the exception of the high variability associated with the volume of distribution of the central compartment, having no effect on the area under the plasma concentration-time curve.
Therapeutic drug monitoring (TDM) of infliximab has been shown to be a effective strategy for inflammatory bowel disease (IBD). Population pharmacokinetic (PopPK) modeling can predict trough ...concentrations for individualized dosing.
The aim of this study was to develop a PopPK model of infliximab in a paediatric population with IBD, assessing the effect of single nucleotide polymorphisms (SNPs) and other biomarkers on infliximab clearance.
This observational and ambispective single-centre study was conducted in paediatric patients with IBD treated with infliximab between July 2016 and July 2022 in the Paediatric Gastroenterology Service of the Hospital Universitari Vall d'Hebron (HUVH) (Spain). Demographic, clinical, and analytical variables were collected. Twenty SNPs potentially associated with variations in the response to infliximab plasma concentrations were analysed. infliximab serum concentrations and antibodies to infliximab (ATI) were determined by ELISA. PopPK modelling was performed using nonlinear mixed-effects analysis (NONMEM).
Thirty patients (21 males) were included. The median age (range) at the start of infliximab treatment was 13 years (16 months to 16 years). A total of 190 samples were obtained for model development (49 25.8% during the induction phase). The pharmacokinetics (PK) of infliximab were described using a two-compartment model. Weight, erythrocyte sedimentation rate (ESR), faecal calprotectin (FC), and the SNP rs1048610 (ADAM17) showed statistical significance for clearance (CL), and albumin for inter-compartmental clearance (Q). Estimates of CL1 (genotype 1-AA), CL2 (genotype 2-AG), CL3 (genotype 3-GG), Q, V
, and V
(central and peripheral distribution volumes) were 0.0066 L/h/46.4 kg, 0.0055 L/h/46.4 kg, 0.0081 L/h/46.4 kg, 0.0029 L/h/46.4 kg, 0.6750 L/46.4 kg, and 1.19 L/46.4 kg, respectively. The interindividual variability (IIV) estimates for clearance, V
, and V
were 19.33, 16.42, and 36.02%, respectively.
A popPK model utilising weight, albumin, FC, ESR, and the SNP rs1048610 accurately predicted infliximab trough concentrations in children with IBD.
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