|Year : 2021 | Volume
| Issue : 2 | Page : 108-114
Prediction of pharmacokinetic values of two various dosages of caffeine in premature neonates with apnea
Fatemeh Faramarzi1, Mohammadreza Shiran2, Mohammadreza Rafati3, Roya Farhadi4, Ebrahim Salehifar3, Maryam Nakhshab4
1 Clinical Pharmacy Research Center, Iran University of Medical Sciences, Tehran, Iran
2 Immunogenetics Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
3 Department of Clinical Pharmacy, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
4 Department of Pediatrics, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
|Date of Submission||29-Sep-2019|
|Date of Decision||23-Jan-2021|
|Date of Acceptance||30-Apr-2021|
|Date of Web Publication||26-May-2021|
Dr. Fatemeh Faramarzi
Clinical Pharmacy Research Center, Iran University of Medical Sciences, Tehran
Source of Support: None, Conflict of Interest: None
Objectives: Despite extensive caffeine use in preterm infants, the pharmacokinetics (PKs) data are limited because of the studies are complicated to do in these patients. This research was investigated the PK profile of two various dosages of caffeine in premature neonates.
Materials AND METHODS: The PK values of caffeine in premature neonates with Apnea were predicted by using all of computer-based simulation (Simcyp®), population-based PK, and modeling (P-Pharm®). We assayed the plasma levels of caffeine in two groups. The information was analyzed utilizing nonlinear mixed-effects modeling approach. The PK parameters were assessed simulating virtual clinical considers with subjects got 20 mg. kg−1 of caffeine in both groups, which was followed by a 5 mg. kg−1 once daily in Group 1 or 2.5 mg. kg−1 twice daily in Group 2. All statistical analysis was executed utilizing SSPS issue 19 and a P value of 0.05 was chosen significance.
Results: In the present study, the means CL, volume of distribution, and T1/2 of caffeine in preterm infants were 0.0476 L. h−1, 1.1081 L, 16.2284 h, respectively. Whereas our simulated means by Simcyp were 0.090 L. h−1, 1.841 L, and 14.653 h in Group 1 and 16.223 h in Group 2, respectively.
Conclusions: There was overall good agreement between predicted and measured PK values in our study. This study provides an initial demonstration of Simcyp simulation advantage on anticipating of PK parameters.
Keywords: Apnea, caffeine, pharmacokinetic, premature neonates
|How to cite this article:|
Faramarzi F, Shiran M, Rafati M, Farhadi R, Salehifar E, Nakhshab M. Prediction of pharmacokinetic values of two various dosages of caffeine in premature neonates with apnea. Indian J Pharmacol 2021;53:108-14
|How to cite this URL:|
Faramarzi F, Shiran M, Rafati M, Farhadi R, Salehifar E, Nakhshab M. Prediction of pharmacokinetic values of two various dosages of caffeine in premature neonates with apnea. Indian J Pharmacol [serial online] 2021 [cited 2021 Jun 16];53:108-14. Available from: https://www.ijp-online.com/text.asp?2021/53/2/108/316952
| » Introduction|| |
Apnea of prematurity is a prevalent disease, result in an imperfection of the respiratory control system and unstable respiratory drive in premature infants.,,,, Caffeine as a favorable methylxanthine has stimulant effects of the respiratory system, which is the standard pharmacological treatment for apnea in premature neonates. The current standard loading and maintenance dosages of caffeine involve a 20 mg per kg and 5 mg per kg per day, respectively.,
A safe therapeutic plasma concentration is in the range of 3 mg/L to 84 mg/L. The defensive effects of caffeine on the brain and lungs are major benefits of caffeine, yet there are few side effects on the preterm infants.,,,,, Caffeine increase the respiratory muscle strength, the diaphragmatic activity, and the tidal volume., Furthermore, it reduces the occurrence of Bronchopulmonary Dysplasia, it decreases the length of continuous positive airway pressure and mechanical ventilation in premature newborns.,,, Despite the extensive use of caffeine in premature neonates, Pharmacokinetics (PKs) data are limited; because these studies are complicated to carry out in these patients. Some of these studies are available.,, It has reported that caffeine clearance (CL) was very slow, and its half-life was prolonged. Another study showed the CL and volume of distribution (Vd) notably impacted by after the birth age and body weight, while Vd was higher in more advanced infants. It has proposed that caffeine improves ventilation in 8–20 mg/L plasma concentration, mostly through improving central respiratory drive. Some studies have examined how various dosages of caffeine can improve the respiratory action of premature newborns; high dose caffeine equivalent to 20 mg per kg per day decreases the require for respiratory backing; meanwhile, the standard dosage regimen (5 mg per kg per day) lead to no adverse results at 2 years old. The higher concentrations are related to the lower duration of hospitalization, time of ventilation, and the time of oxygen at discharge. It has shown that the caffeine concentration is not related to the frequency of apnea within 7 days of the drug discontinuation, the therapeutic range is 11–12 days. Nevertheless, studies of caffeine PKs regarding the premature infant were limited and there is little data available. Therefore, this research was planned to investigate the PKs profile of caffeine in premature neonates. Moreover, we assayed the plasma levels and the divided caffeine dosing regimens in these patients.
| » Materials and Methods|| |
This study conducted at neonatal intensive care center of Boo-Ali Sina Pediatrics Hospital, from July 2015 to August 2016. Patients between the ages of 26–37 weeks entered into the trial with evidence of apnea, and they had been administered caffeine by a neonatologist. Patients with the following conditions were excluded from the study; having underlying diseases, treatment with methylxanthine in the past. Caffeine was from Chemidarou Pharmaceutical Co. Ltd., (Tehran, Iran). Perchloric acid and methanol for High-performance liquid chromatography (HPLC) were prepared from Merck (Darmstadt, Germany). Deionized water utilized in the procurement of mobile phase. Blank plasma utilized for calibration and approval of the trial was gotten from Healthy volunteers. Forty infants were randomized into two groups, each group gotten a loading dose of 20 mg per kg of caffeine intravenously for the primary ½ h, taken after a maintenance dose of 5 mg per kg daily for Group 1 and 2.5 mg per kg twice daily for Group 2 over 20 min.
The PKs values for caffeine in premature neonates with apnea were predicted by utilizing all of computer-based simulation (Simcyp®), population-based (PB)-PK and modeling (P-Pharm®). The study protocol was morally approved. As well as an informed signed consent was approved by all patients' parents.
Up to 3 blood samples were drawn from each patient via peripheral vein after 30 min of the loading dose, 30 min after the first maintenance dose, and 72 h after initiation of caffeine, the initiation of caffeine must be before intravenous (IV) administration. Plasma was provided and maintained at −20°C till analysis.
Plasma concentrations of caffeine were determined using the Euro chrome software of HPLC on a Knauer C8 column with 150 × 4 millimeter i. d. and 5 micrometer bit dimension. The mobile phase comprised methyl alcohol and distilled water (pH = 6) (30/70, v/v). The calibration range of the assay was 50–1000 ng ml. Examinations operate at a flow rate of 0.9 ml per min at environment temperature. The wavelength was put on 280 nm, and the peak areas were gauged. The working solution of caffeine citrate attenuated with drug-free plasma to impute the calibration standards at concentrations of 10, 20, 30, 40, and 50 μg/ml caffeine.
Population pharmacokinetic analysis
This study also employed a small exampling trial plan to assessment caffeine PK parameters. Caffeine concentration information over the time was assayed utilizing nonlinear mixed-effects model, which was executed in P-PHARM French issue 1.5.1 software. The PKs parameters of caffeine were assessed simulating virtual clinical trials with subjects getting 20 mg per kg loading dose of the drug in two groups, which was continued with 5 mg per kg dose of the drug once daily in the first series of patients or 2.5 mg per kg twice a day in the second series of patients.
Simulations of pharmacokinetic profiles of caffeine using Simcyp®
Caffeine PKs was simulated utilizing the full PB PK pattern executed in the Simcyp Pediatric PB Simulator (issue 13.2, UK). In vitro information portraying the physicochemical properties of caffeine is summarized in [Table 1]. Age, dosage, dosage spacing, and duration of caffeine injection put confirming to the clinical study. Patient's simulations were executed utilizing 500 patients aged <1 month, in 10 trials, with each trial containing 50 subjects. All parameters were achieved from the pediatric patient's library inside a pediatric issue of Simcyp. A summary of input parameters in Simcyp is shown in [Table 2].
Qualitative factors were registered by frequency and percent and quantitative factors by mean ± standard deviations. Whole statistical analyses were executed utilizing SPSS issue 19 (SPSS Inc., Chicago, IL, USA). The level of significance of 5% was selected. Caffeine concentration information over the time was assayed utilizing nonlinear mixed-effects model, which was executed in P-PHARM French issue 1.5.1 software. PK information was coordinated with various PK patterns and the most compatible pattern elected.
| » Results|| |
Forty-seven neonates listed in this trial and forty patients complied trial criteria. Seven of them divested the study; two neonates because of hypoglycemia, two of the seven patients due to congenital anomaly, one of them were divested due to his intra-ventricular hemorrhage, and two patients due to death. Demographic and clinical properties of patients in two series are displayed in [Table 3].
|Table 3: Demographic and clinical characteristics of the patients in two study groups|
Click here to view
Statistical analysis revealed that there was no statistically significant difference in terms of clinical properties among patients of two groups (P ≥ 0.2).
Population pharmacokinetic analysis
A one-compartment steady-state PK pattern with first-level dispensational level constants and first-level elimination supplied a notably suitable concentration-time profile than other patterns. A Heteroscedastic error model (1/y^2) was fitting for all the measures. A lognormal dispensation best explained the inter-person variation in all population pharmacokinetic (POPPK) parameters. The population-derived Bayesian predicted versus observed total plasma concentrations at steady state is appeared in [Figure 1].
|Figure 1: The population-derived Bayesian predicted versus observed total plasma concentrations of caffeine at steady state calculated from best-fitted model|
Click here to view
After coordinating the one compartment model, the predicted plasma concentrations of caffeine were followed by IV infusion with 24 h (study 1) and 12 h (study 2) intervals displayed in [Figure 2].
|Figure 2: The predicted total plasma concentrations curve of caffeine after fitting to the one –compartment model following intravenous administration with 24 h (study 1) or 12 h intervals (study 2)|
Click here to view
The present HPLC assay is simple, sensitive, and gave chromatograms with adequate separation of caffeine. A representative chromatogram of the drug is shown in [Figure 3]. Under the chromatographic situation utilized, caffeine (retention time 8.18 ± 0.042 min), gave quickly eluting, entirely settled, and basically symmetrical peaks [Figure 4]. Calibration curves for the caffeine over known concentration span were linear (R2 = 0.998) [Figure 3].
|Figure 3: Representative calibration curves for the analysis of caffeine by high-performance liquid chromatography|
Click here to view
|Figure 4: Reconstructed chromatogram following the analysis of blank plasma spiked with 40 μg/ml of caffeine|
Click here to view
Simulations of pharmacokinetic profiles of caffeine using Simcyp®
The Simcyp® simulation was conducted using a design that reflected the clinical study design of caffeine. The mean plasma concentrations of caffeine after simulation by SIMCYP followed by IV infusion with 24 (study 1) and 12 (study 2) h intervals are shown in [Figure 5].
|Figure 5: Systemic simulated the mean plasma concentrations of caffeine after intravenous infusion with 24 and 12 h intervals|
Click here to view
The mean values of PKs parameters of caffeine in 500 virtual subjects simulated from in vitro data using SIMCYP software after IV infusion with 12 and 24 h intervals are presented in [Table 4].
|Table 4: Mean values of pharmacokinetic parameters of caffeine in 500 virtual subjects simulated from in vitro data using simcyp|
Click here to view
Pharmacokinetic parameter values for caffeine
A summary of PK parameters includes T1/2 beta, a Vd and CL of caffeine in our infant patients following 24-h or 12 h intervals of drug administration are shown in [Table 5].
|Table 5: A summary of pharmacokinetic parameters of caffeine in preterm infants after 24-h (Study 1) or 12 h (Study 2) IV infusion of the drug|
Click here to view
| » Discussion|| |
In this trial, we investigated the PK profile of caffeine after intravenous administration in preterm neonates with apnea. Several studies have indicated the PKs of caffeine in premature neonates.
Aranda et al., in 1979, reviewed the PK profile of caffeine by using a first-order one-compartment model in preterm infants. Based on results, the mean CL, Vd and T½ values of caffeine were estimated to be 8.9 ml per h per kg (0.0089 L. h−1.kg−1), 0.916 L. kg−1 and 102.9 h, respectively. Gorodischer studied the PKs of caffeine in 1982 in 13 premature infants with apnea. Caffeine CL was very slow, and its half-life was prolonged. The mean CL, distribution volume, and plasma half-life values of caffeine were estimated 8.5 ml per hour per kg (0.0085 L. h−1.kg−1), 0.78 L. kg−1 and 65 h, respectively. Lee et al. have evaluated POPPK modeling of caffeine in premature neonates with apnea in 1997. The analysis was performed using NONMEM to estimate the parameters of the one compartment model. CL (0.012 L. h−1) and distribution volume (2.2 L) notably related to after the birth age and body weight while distribution volume was higher in more advanced neonates and half-life was 144 h. In another study which carried out in 18 Asian preterm infants using P-Pharm software and a one-compartment model. The population means CL, Vd and T1/2 values of caffeine were estimated 0.00638 L. h−1, 0.9608 L, and 106 h, respectively. Falcao et al. performed a POPPK study of caffeine in premature neonates. The analysis was carried out based on a non-linear mixed effect model (NONMEN) and one-compartment model. The values included: CL (L. h−1) = 0.00581* current weight (kg) +1.22* after the birth age (weeks) and distribution volume (L) = 0.911* current weight (kg). The POPPKs of caffeine were studied in 60 infants. CL affected by body weight and after the birth age. Cl and Vd of caffeine stay constant during the treatment. A final analysis proved CL (Litter per hour) = 0.015 and distribution volume = 0.82 Litter. A POPPKs model of caffeine was surveyed in premature neonates by Charles et al. PK values were estimated using a one-compartment model of NONMEN. CL enhanced nonlinearly with incrementing postnatal age, while distribution volume (Vd) enhanced linearly with weight, agreeing to next allometric models: CL (L. h−1) =0.016; Vd (L) =1.76. The mean of elimination half-life reported 101 h. PK parameters of caffeine in premature neonates were reported by Patel et al. The POPPK model obtained using NONMEN. Final model was as follows: CL = 0.015 (L. h−1), Vd (L) =1.29, T1/2 (h) =57. A POPPK model was studied utilizing NONMEM in 29 infants. The PK values were calculated based on final mode: CL (L. h−1) =0.0167, Vd (L) = 0.966. In the present study, the population means CL, the Vd and half-life values of caffeine in premature neonates with apnea were 0.0476 (L. h−1), 1.1081 (L), and 16.2284 (h) respectively [Table 5]. The CL in our infants was larger than reported in previously mentioned studies. The distribution volume per kilogram was approximately alike with amounts detailed already for newborns.,,, However, the half-life of caffeine in this study was lower than in other studies. Regarding daily administration of caffeine in premature newborns that is routine, the half-life of 16 h seems to be more acceptable than the higher values.
The second target of the study was to compare predicted and observed PK parameters of caffeine in preterm infants with apnea. Several researchers have represented different approaches whereby PK parameters can be estimated from in vitro data. In these studies, many ways have been utilized to predict the values.,,,,, Accurate predictions can result in reducing the costs and times that required for clinical trials.
| » Conclusions|| |
This trial was carried out to assess the PK parameters of caffeine in premature newborns, which was executed in parallel with a clinical trial to assess the therapeutic outcomes of caffeine on apnea of prematurity. In the present study, the population means CL, Vd and T1/2 values of caffeine in premature newborns with apnea were 0.0476 L. h−1, 1.1081 L, and 16.2284 h, respectively. Whereas our simulated mean CL, V, and Ka values by Simcyp were 0.090 L. h−1, 1.841 L, and 14.653 h in Group 1 and 16.223 h in Group 2, respectively. There was overall good matching among predicted and measured PKs measures in our study. Furthermore, Cmax in Group 1 and 2 was 6033.09 and 9476.39 ng/ml respectively in simulated patients. However, the value of Cmax in the patients was not available because of the low number or volume of some blood samples. Given the limitations of clinical trials, especially in premature infants, this can be justified. The present study provides an initial demonstration of the potential advantage of Simcyp simulation on predicting of drugs PK parameters especially on predicting of half-life.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Finer NN, Higgins R, Kattwinkel J, Martin RJ. Summary proceedings from the apnea-of-prematurity group. Pediatrics 2006;117:S47-51.
Eichenwald EC; Committee on Fetus and Newborn, American Academy of Pediatrics. Apnea of prematurity. Pediatrics 2016;137:e20153757.
Atkinson E, Fenton AC. Management of apnoea and bradycardia in neonates. Paediatr Child Health 2009;19:550-4.
Zhao J, Gonzalez F, Mu D. Apnea of prematurity: From cause to treatment. Eur J Pediatr 2011;170:1097-105.
Mathew OP. Apnea of prematurity: Pathogenesis and management strategies. J Perinatol 2011;31:302-10.
Dobson NR, Hunt CE. Pharmacology review: Caffeine use in neonates: Indications, pharmacokinetics, clinical effects, outcomes. Neoreviews 2013;14:540-50.
Gare S, Lal M, Tin W. Apnoea in premature infants and caffeine therapy. Infant 2013; 9: 9-12.
Kahn DJ, Godin R. Is it time to embrace the caffeine level? Pediatrics 2016;137:e20160403A.
Aranda JV, Cook CE, Gorman W, Collinge JM, Loughnan PM, Outerbridge EW, et al.
Pharmacokinetic profile of caffeine in the premature newborn infant with apnea. J Pediatr 1979;94:663-8.
Mueni E, Opiyo N, English M. Caffeine for the management of apnea in preterm infants. Int Health 2009;1:190-5.
Johnson PJ. Caffeine citrate therapy for apnea of prematurity. Neonatal Netw 2011;30:408-12.
Orozco-Gregorio H, Mota-Rojas D, Villanueva D, Bonilla-Jaime H, Suarez-Bonilla X, Torres-González L, et al.
Caffeine therapy for apnoea of prematurity: Pharmacological treatment. Afr J Pharm Pharm 2011;5:564-7.
Pacifici GM. Clinical pharmacology of caffeine citrate in preterm infants. Med Exp 2014;1:243-50.
Abdel-Hady H, Nasef N, Shabaan AE, Nour I. Caffeine therapy in preterm infants. World J Clin Pediatr 2015;4:81-93.
Kassim Z, Greenough A, Rafferty GF. Effect of caffeine on respiratory muscle strength and lung function in prematurely born, ventilated infants. Eur J Pediatr 2009;168:1491-5.
Kraaijenga JV, Hutten GJ, de Jongh FH, van Kaam AH. The effect of caffeine on diaphragmatic activity and tidal volume in preterm infants. J Pediatr 2015;167:70-5.
Aranda JV, Gorman W, Bergsteinsson H, Gunn T. Efficacy of caffeine in treatment of apnea in the low-birth-weight infant. J Pediatr 1977;90:467-72.
Lista G, Fabbri L, Polackova R, Kiechl-Kohlendorfer U, Papagaroufalis K, Saenz P, et al.
The real-world routine use of caffeine citrate in preterm infants: A European postauthorization safety study. Neonatology 2016;109:221-7.
Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, et al.
Caffeine therapy for apnea of prematurity. N Engl J Med 2006;354:2112-21.
Lee HS, Khoo YM, Chirino-Barcelo Y, Tan KL, Ong D. Caffeine in apnoeic Asian neonates: A sparse data analysis. Br J Clin Pharmacol 2002;54:31-7.
Gorodischer R, Karplus M. Pharmacokinetic aspects of caffeine in premature infants with apnoea. Eur J Clin Pharmacol 1982;22:47-52.
Lee TC, Charles B, Steer P, Flenady V, Shearman A. Population pharmacokinetics of intravenous caffeine in neonates with apnea of prematurity. Clin Pharmacol Ther 1997;61:628-40.
Aranda JV, Turmen T, Davis J, Trippenbach T, Grondin D, Zinman R, et al.
Effect of caffeine on control of breathing in infantile apnea. J Pediatr 1983;103:975-8.
Gray PH, Flenady VJ, Charles BG, Steer PA; Caffeine Collaborative Study Group. Caffeine citrate for very preterm infants: Effects on development, temperament and behaviour. J Paediatr Child Health 2011;47:167-72.
Alur P, Bollampalli V, Bell T, Hussain N, Liss J. Serum caffeine concentrations and short-term outcomes in premature infants of ≤29 weeks of gestation. J Perinatol 2015;35:434-8.
Doyle J, Davidson D, Katz S, Varela M, Demeglio D, DeCristofaro J. Apnea of prematurity and caffeine pharmacokinetics: Potential impact on hospital discharge. J Perinatol 2016;36:141-4.
Falcão AC, Fernández de Gatta MM, Delgado Iribarnegaray MF, Santos Buelga D, García MJ, Dominguez-Gil A, et al.
Population pharmacokinetics of caffeine in premature neonates. Eur J Clin Pharmacol 1997;52:211-7.
Thomson AH, Kerr S, Wright S. Population pharmacokinetics of caffeine in neonates and young infants. Ther Drug Monit 1996;18:245-53.
Charles BG, Townsend SR, Steer PA, Flenady VJ, Gray PH, Shearman A. Caffeine citrate treatment for extremely premature infants with apnea: Population pharmacokinetics, absolute bioavailability, and implications for therapeutic drug monitoring. Ther Drug Monit 2008;30:709-16.
Patel P, Mulla H, Kairamkonda V, Spooner N, Gade S, Della Pasqua O, et al.
Dried blood spots and sparse sampling: A practical approach to estimating pharmacokinetic parameters of caffeine in preterm infants. Br J Clin Pharmacol 2013;75:805-13.
Dobson NR, Liu X, Rhein LM, Darnall RA, Corwin MJ, McEntire BL, et al.
Salivary caffeine concentrations are comparable to plasma concentrations in preterm infants receiving extended caffeine therapy. Br J Clin Pharmacol 2016;82:754-61.
Bouzom F, Walther B. Pharmacokinetic predictions in children by using the physiologically based pharmacokinetic modelling. Fundam Clin Pharmacol 2008;22:579-87.
Houston JB, Galetin A. Progress towards prediction of human pharmacokinetic parameters from in vitro
technologies. Drug Metab Rev 2003;35:393-415.
De Buck SS, Sinha VK, Fenu LA, Nijsen MJ, Mackie CE, Gilissen RA. Prediction of human pharmacokinetics using physiologically based modeling: A retrospective analysis of 26 clinically tested drugs. Drug Metab Dispos 2007;35:1766-80.
Poulin P, Theil FP. Prediction of pharmacokinetics prior to in vivo
studies. II. Generic physiologically based pharmacokinetic models of drug disposition. J Pharm Sci 2002;91:1358-70.
Rostami-Hodjegan A. Physiologically based pharmacokinetics joined with in vitro
extrapolation of ADME: A marriage under the arch of systems pharmacology. Clin Pharmacol Ther 2012;92:50-61.
Rostami-Hodjegan A, Tucker GT. Simulation and prediction of in vivo
drug metabolism in human populations from in vitro
data. Nat Rev Drug Discov 2007;6:140-8.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]