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In the last 20 years, modeling and simulations (M&S) have gained increased attention in pharmaceutical sciences. International industry and world-reference agencies have used M&S to make cost-efficient decisions through the model-informed drug development (MIDD) framework. Modeling tools include biopredictive dissolution models, physiologically based pharmacokinetic models (PBPK), biopharmaceutic models (PBBM), and virtual bioequivalence, among many others. Regulatorily, health agencies are becoming more and more open to accept the use of M&S to support regulatory applications, including setting dissolution specifications, quality-by-design (QbD), postapproval changes (SUPAC), etc. Nonetheless, the potential of M&S has been only barely explored in Latin America (Latam) across different actors: industry, regulatory agencies, and even academia. In this manuscript, we discuss the challenges and opportunities for implementing M&S approaches in Latam. Perspectives of regional experts were shared in a workshop. Attendance (professionals from industry, regulator, academia, and clinicians) also shared their views via survey. The rational development of bioequivalent generics was considered the main opportunity for M&S in regional market, particularly the use of PBPK and PBBM. Nonetheless, a critical mass of modeling scientists is needed before Latin American industry and regulators can actually benefit from M&S. Collaborations (e.g., Academia-Industry and Academia-Regulatory) may be a path to develop applied research projects and train the future modelers. Reaching that critical mass, scientists from industry may apply modeling across generic drug development process and life cycle, while regulatory scientists may issue guidelines in local language to support regional industry. Only at that stage could the full potential of MIDD be reached in Latin American generic markets.

Background: The Nociception Level Index has shown benefits in estimating the nociception/antinociception balance in adults, but there is limited evidence in the pediatric population. Evaluating the index performance in children might provide valuable insights to guide opioid administration., Aims: To evaluate the Nociception Level Index ability to identify a standardized nociceptive stimulus and the analgesic effect of a fentanyl bolus. Additionally, to characterize the pharmacokinetic/pharmacodynamic relationship of fentanyl with the Nociception Level Index response during sevoflurane anesthesia., Methods: Nineteen children, 5.3 (4.1-6.7) years, scheduled for lower abdominal or urological surgery, were studied. After sevoflurane anesthesia and caudal block, a tetanic stimulus (50 Hz, 60 mA, 5 s) was performed in the forearm. Following the administration of fentanyl 2 μg/kg intravenous bolus, three similar consecutive tetanic stimuli were performed at 5-, 15-, and 30-min post-fentanyl administration. Changes in the Nociception Level Index, heart rate, mean arterial pressure, and bispectral index were compared in response to the tetanic stimuli. Fentanyl plasma concentrations and the Nociception Level Index data were used to elaborate a pharmacokinetic/pharmacodynamic model using a sequential modeling approach in NONMEM®., Results: After the first tetanic stimulus, both the Nociception Level Index and the heart rate increased compared to baseline (8 ± 7 vs. 19 ± 10; mean difference (CI95) -12(-18--6) and 100 ± 10 vs. 102 ± 10; -2(-4--0.1)) and decrease following fentanyl administration (19 ± 10 vs. 8 ± 8; 12 (5-18) and 102 ± 10 vs. 91 ± 11; 11 (7-16)). In subsequent tetanic stimuli, heart rate remained unchanged, while the Nociception Level Index progressively increased within 15 min to values similar to those before fentanyl. An allometric weight-scaled, 3-compartment model best characterized the pharmacokinetic profile of fentanyl. The pharmacokinetic/pharmacodynamic modeling analysis revealed hysteresis between fentanyl plasma concentrations and the Nociception Level Index response, characterized by plasma effect-site equilibration half-time of 1.69 (0.4-2.9) min. The estimated fentanyl C50 was 1.93 (0.73-4.2) ng/mL., Conclusion: The Nociception Level Index showed superior capability compared to traditional hemodynamic variables in discriminating different nociception-antinociception levels during varying fentanyl concentrations in children under sevoflurane anesthesia., (© 2024 John Wiley & Sons Ltd.)

An effect-site target-controlled infusion (TCI) would allow a more precise titration of intravenous analgesics effect. The analgesia nociception index (ANI) continuously monitors the analgesia/nociception balance during general anesthesia. This study aims to derive a PKPD model of ketamine antinociceptive effect using the Domino PK parameter set and the ANI response data in awake patients without other drugs affecting the ANI response. Twenty awake adult patients were prospectively studied before general anesthesia. Patients received a single intravenous bolus of ketamine 0.1 mg·kg - 1 , and the subsequent ANI values were recorded. An effect compartment model incorporating the Domino PK parameter set was used to characterize the time lag between ketamine plasma concentrations and the ANI response. The model was parameterized with a single parameter Ke0. An Emax pharmacodynamic model was used to fit the ANI response data. Model parameters were estimated with NONMEM ® 7.5. The minimum objective function value guided the model construction. After the ketamine administration, basal ANI values increased from 38.5 ± 4.95 to a maximum of 53.5 ± 4.95 with an observed time-to-peak effect of 1.83 ± 0.74 min. Modeling analysis revealed hysteresis between predicted plasma concentrations from the Domino model and observed ANI data. Hysteresis was characterized, incorporating an estimated Keo of 0.238 (CI95% 0.20-0.28) min-1 to the described PK parameters set. The developed PKPD model, using Domino's PK parameters and the ANI response data, adequately characterized the temporal profile of ketamine's antinociceptive effect. The current estimated model parameters can be used to perform an effect-site TCI of ketamine for analgesic purposes., Competing Interests: Declarations Ethical approval This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Clínica Central Cira García, La Habana, Cuba. (October 30th, 2021). Consent to participate Informed consent was obtained from all individual participants included in the study. Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Aims: This study aimed to characterize the population pharmacokinetic parameters of intravenously administered amikacin in newborns and assess the effect of sepsis in amikacin exposure., Methods: Newborns aged ≥3 days who received at least 1 dose of amikacin during their hospitalization period were eligible for the study. Amikacin was administered intravenously during a 60-min infusion period. Three venous blood samples were taken from each patient during the first 48 h. Population pharmacokinetic parameter estimates were obtained using a population approach with the programme NONMEM., Results: Data from 329 drug assay samples were obtained from 116 newborn patients (postmenstrual age [PMA] 38.3, range 32-42.4 weeks; weight 2.8, range 1.6-3.8 kg). Measured amikacin concentrations ranged from 0.8 to 56.4 mg/L. A 2-compartment model with linear elimination produced a good fit of the data. Estimated parameters for a typical subject (2.8 kg, 38.3 weeks) were clearance (Cl = 0.16 L/h), intercompartmental clearance (Q = 0.15 L/h), volume of distribution of the central compartment (Vc = 0.98 L) and peripheral volume of distribution (Vp = 1.23 L). Total bodyweight, PMA and the presence of sepsis positively influenced Cl. Plasma creatinine concentration and circulatory instability (shock) negatively influenced Cl., Conclusion: Our main results confirm previous findings showing that weight, PMA and renal function are relevant factors influencing newborn amikacin pharmacokinetics. In addition, current results showed that pathophysiological states of critically ill neonates, such as sepsis and shock, were associated with opposite effects in amikacin clearance and should be considered in dose adjustments., (© 2023 British Pharmacological Society.)

The present study aimed to analyze the effect of static and dynamic stretching exercises on the rate of force development (RFD) during the eccentric braking phase and jump height in a countermovement jump (CMJ) in female volleyball players. Thirty female volleyball players were randomly distributed in a static stretching (n = 10; SG), a dynamic stretching, and (n = 10; DG) a control group (n = 10; CG). A force plate and a 3D analysis system were employed to detect the eccentric braking phase during the CMJ. The RFD was analyzed in RFD (RFDi) intervals and the accumulated RFD (RFDa), and normalized to body mass. The SG experienced a likely small decrease in the RFDa (mean difference -17.4 N/s/kg) and a likely small decrease in the RFDi (mean difference -19.1 N/s/kg). Contrarily, the DG showed a likely small increase in the RFDa (mean difference 31.2 N/s/kg) and a most likely small increase in the RFDi (mean difference 34.8 N/s/kg). The effect of both static and dynamic stretching on jump height was trivial. Practitioners should consider utilizing dynamic stretching exercises instead of static stretching before a competition in female volleyball players. Further research is needed in order to find complementary strategies during the warm-up that could increase jump height., (© 2022 Mauricio Araya-Ibacache, Esteban Aedo-Muñoz, Pablo Carreño-Ortiz, Christopher Moya-Jofré, Amaya Prat-Luri, Hugo Cerda-Kohler, published by Sciendo.)