Multistep Unified Models Using Prior Knowledge for the Prediction of Drug Clearance in Neonates and Infants

Tegenge, Million A.; Mahmood, Iftekhar; Jiang, Zhen; Forshee, Richard A.

doi:10.1002/jcph.1089

Cited by 7 publications

(5 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We noted a relatively less precise prediction of clearance in children ≤2 years of age vs older children (>2 years of age). This is not surprising since previously published allometric, mechanistic, and PBPK models also demonstrated similar observations 16,30–33 . For example, a comparison between PBPK and allometric scaling (using an age‐dependent exponent) showed that both models provided a similar magnitude of precision for clearance prediction in children ≤2 years of age, which was slightly lower than the older children 16 .…”

Section: Discussionsupporting

confidence: 61%

Spreadsheet‐Based Minimal Physiological Models for the Prediction of Clearance of Therapeutic Proteins in Pediatric Patients

Mahmood¹,

Tegenge

2021

The Journal of Clinical Pharma

Self Cite

View full text Add to dashboard Cite

There is a growing interest in the use of physiologically based pharmacokinetic (PBPK) models as clinical pharmacology drug development tools. In PBPK modeling, not every organ or physiological parameter is required, leading to the development of a minimal PBPK (mPBPK) model, which is simple and efficient. The objective of this study was to streamline mPBPK modeling approaches and enable straightforward prediction of clearance of protein‐based products in children. Four mPBPK models for scaling clearance from adult to children were developed and evaluated on Excel spreadsheets using (1) liver and kidneys; (2) liver, kidneys, and skin; (3) liver, kidneys, skin, and lymph; and (4) interstitial, lymph, and plasma volume. There were 35 therapeutic proteins with a total of 113 observations across different age groups (premature neonates to adolescents). For monoclonal and polyclonal antibodies, more than 90% of observations were within a 0.5‐ to 2‐fold prediction error for all 4 methods. For nonantibodies, 79% to 100% of observations were within the 0.5‐ to 2‐fold prediction error for the 4 different methods. Methods 1 and 4 provided the best results, >90% of the total observations were within the 0.5‐ to 2‐fold prediction error for all 3 classes of protein‐based products across a wide age range. The precision of clearance prediction was comparatively lower in children ≤2 years of age vs older children (>2 years of age) with methods 1 and 4 predicting 80% to 100% and 75% to 90% of observations within the 0.5‐ to 2‐fold prediction error, respectively. The results of the study indicated that mPBPK models can be developed on spreadsheets, with acceptable performance for prediction of clearance.

show abstract

Section: Discussionsupporting

confidence: 61%

Spreadsheet‐Based Minimal Physiological Models for the Prediction of Clearance of Therapeutic Proteins in Pediatric Patients

Mahmood¹,

Tegenge

2021

The Journal of Clinical Pharma

Self Cite

View full text Add to dashboard Cite

show abstract

“…Such preliminary data combined with further clinical validation could provide information on clinical drug medication in neonates. 47,48…”

Section: Discussionmentioning

confidence: 99%

Cross-sectional study of drug utilisation in a Chinese neonatal unit

et al. 2020

View full text Add to dashboard Cite

Objective This study aimed to describe drug utilisation in a large Chinese neonatal unit and to compare the findings with those from other countries. Methods Data were collected from electronic medical records. Prescription drugs were defined as the number of unique medication names for each patient. Medicine doses were defined as the total number of doses of all medicines administered. Information was collected regarding drugs prescribed to inpatients between March 1 and April 1 2018 in the neonatal intensive care unit and the general neonatal ward of West China Second University Hospital. Results The 319 neonates received 1276 prescription drugs and 11,410 medicine doses involving 81 drugs. Vitamin K1, hepatitis B vaccine, and cefoperazone-sulbactam were the three most frequently prescribed drugs. Antimicrobials were the most frequently used group of medicines, with cefoperazone-sulbactam and piperacillin-tazobactam the most frequently used in an off-label manner. Domperidone and simethicone were both widely used. Conclusions The most commonly prescribed antimicrobials differed greatly from those reported for other countries. The evidence base for the use of some medicines is poor, and is indicative of irrational prescribing.

show abstract

“…To calculate the optimal doses, we used the range of 0.3–0.6 μg/L as the PK target for efficacious and safe analgesia [21], while higher levels have been described for anaesthetic effects in the literature [26]. Currently, the usual induction and maintenance doses of sufentanil are 0.25–2.0 and 0.5–1.5 μg/kg/h, respectively [11, 27-29]. Our results indicate that the respective doses of 2.13 μg/kg and 0.29 μg/kg/h could be used.…”

Section: Discussionmentioning

confidence: 99%

Sufentanil Disposition and Pharmacokinetic Model-Based Dosage Regimen for Sufentanil in Ventilated Full-Term Neonates

et al. 2021

View full text Add to dashboard Cite

Introduction: Sufentanil is a potent synthetic opioid used for analgesia in neonates; however, data concerning drug disposition of sufentanil and dosage regimen are sparse in this population. Therefore, the aim of the study was to explore sufentanil disposition and to propose optimal loading and maintenance doses of sufentanil in ventilated full-term neonates. Methods: Individual sufentanil pharmacokinetic parameters were calculated based on therapeutic drug monitoring data using a 2-compartmental model. Linear regression models were used to explore the covariates. Results: The median (IQR) central volume of distribution (Vdc) and clearance (CL) for sufentanil were 4.7 (4.1–5.4) L/kg and 0.651 (0.433–0.751) L/h/kg, respectively. Linear regression models showed relationship between Vdc (L) and GA (r2 = 0.3436; p = 0.0452) as well as BW (r2 = 0.4019; p = 0.0268). Median optimal sufentanil LD and MD were 2.13 (95% CI: 1.78–2.48) μg/kg and 0.29 (95% CI: 0.22–0.37) μg/kg/h, respectively. Median daily COMFORT-B (IQR) scores ranged from 6 to 23 while no significant relationship between pharmacokinetic parameters and COMFORT-B scores was found. Discussion/Conclusion: Body weight and gestational age were found as weak covariates for sufentanil distribution, and the dosage regimen was developed for a prospective trial.

show abstract

Multistep Unified Models Using Prior Knowledge for the Prediction of Drug Clearance in Neonates and Infants

Cited by 7 publications

References 24 publications

Spreadsheet‐Based Minimal Physiological Models for the Prediction of Clearance of Therapeutic Proteins in Pediatric Patients

Spreadsheet‐Based Minimal Physiological Models for the Prediction of Clearance of Therapeutic Proteins in Pediatric Patients

Cross-sectional study of drug utilisation in a Chinese neonatal unit

Sufentanil Disposition and Pharmacokinetic Model-Based Dosage Regimen for Sufentanil in Ventilated Full-Term Neonates

Contact Info

Product

Resources

About