Pharmacokinetics in children

Cloyd, J.C., Fischer, J.H., Kriel, R.L., and Kraus, D.M. (1993) Valproic acid pharmacokinetics in children. IV. Effects of age and antiepileptic drugs on protein binding and intrinsic clearance. Clin Pharmacol Ther 53 22-29. 

Clein, P.D. and Riddle, M.A. (1995) Pharmacokinetics in children and adolescents. Child Adolesc Psychiatr Clin North Am 4 59-75. 

Of all psychiatric medications, the psychostimulants have been the best studied in terms of their pharmacokinetics in children and adolescents (Table 14-4). Next have been studies of antidepressants, while few studies have been done on the pharmacokinetics of antipsychotics and anxiolytics in this age range. 

Beach BJ, Woods WG, Howell SB. Influence of cotrimoxazole on methotrexate pharmacokinetics in children with acute lymphoblastic leukemia. Am J Pediatr Hematol Oncol 1981 3 115-119. 

Frazier JA, Cohen LG, Jacobsen L, Grothe D, Flood J, Baldessarini RJ, Piscitelli S, Kim GS, Rapoport JL. Clozapine pharmacokinetics in children and adolescents with childhood-onset schizophrenia. J Clin Psychopharmacol 2003 23 87-91. 

Routledge P. Pharmacokinetics in children. J Antimi-crob Chemother 1994 34(suppl A) 19-24. 

The two factors responsible for increasing risks of ADRs in children are pharmacokinetic changes and dose delivery issues. Age-related differences in pharmacokinetics in children are documented. However, the data on both efficacy and safety are often limited or not studied at all in this population. Thus, it is unclear whether an increased risk for ADRs exists in this group. However, there is a potential risk for increased ADRs if appropriate considerations are not taken into account in view of pharmacokinetic changes. ... 

Primaquine is rapidly absorbed, extensively distributed, and predominantly cleared by non-renal elimination. Its principal metabolite is carboxyprimaquine. While primaquine itself is rapidly eliminated from the plasma, the drug is effective when given once daily or even once weekly (SEDA-13, 810). The pharmacokinetics in children, pregnant women, and patients with renal or hepatic dysfunction are unknown. 

J. S. Sidhu, M. Ashton, N. V. Huong, et al.. Artemisinin population pharmacokinetics in children and adults with uncomplicated falciparum malaria. Br I Clin Pharmacol 45 347-354 (1998). 

M. F. Delgado Iribarnegaray, D. Santo Bueldga, M. J. Garcia Sanchez, M. J. Otero, A. C. Falcao, and A. Dominguez-Gil, Carbamazepine population pharmacokinetics in children mixed-effect models. Ther Drug Monit 19 132-139 (1997). 

Jacobs RF, Trang JM, Kearns GL, et al. Ticarcillin/clavulanic acid pharmacokinetics in children and young adults with cystic fibrosis. J Pediatr 1985 106 1001-1007. 

Dosage, safety, and efficacy in children have not been established. However, it has been shown to be sate and effective in reversing procedural sedation in chiidren when given in postoperative incremental doses of 0.25 mcg/kg every 2-5 minutes to a maximum total dose of 1 mcg/kg. Nalmefene has similar pharmacokinetics in children as in adults. 

Prasad, V.K. Corlett, S.A. Abaasi, K. Heney, D. Lewis, I. Chrystyn, H. Ifosfamide enantiomers pharmacokinetics in children. Cancer Chemother. Pharmacol 1994, 54, 447 49. 

Yule SM, Boddy AV, Cole M, Price L,WyllieR, Tasso MJ, Pearson ADJ, Idle JR. Cyclophosphamide pharmacokinetics in children. BrJ Clin Pharmacol 996)A, 13-19. 

Ogbom MR, Crocker JFS, Grimm PC. Nifedipine, verapamil and cyclosporin A pharmacokinetics in children. Pediatr Nephrol (1989) 3, 314-16. 

No data were located concerning whether pharmacokinetics of endosulfan in children are different from adults. There are no adequate data to determine whether endosulfan or its metabolites can cross the placenta. Studies in animals addressing these issues would provide valuable information. Although endosulfan has been detected in human milk (Lutter et al. 1998), studies in animals showed very little accumulation of endosulfan residues in breast milk (Gorbach et al. 1968 Indraningsih et al. 1993), which is consistent with the rapid elimination of endosulfan from tissues and subsequent excretion via feces and urine. There are no PBPK models for endosulfan in either adults or children. There is no information to evaluate whether absorption, distribution, metabolism, or excretion of endosulfan in children is different than in adults. 

Inhaled tobramycin (TOBI ) is typically administered to patients 6 years of age and older in alternating 28-day cycles of 300 mg nebulized twice daily, followed by a 28-day washout or off period to minimize development of resistance. Longterm intermittent administration improves pulmonary function, decreases microbial burden, and reduces the need for hospitalization for IV therapy.24,25 Due to minimal systemic absorption, pharmacokinetic monitoring is not necessary with normal renal function. Lower doses of nebulized tobramycin solution for injection have been used in younger children, and studies are underway using 300 mg twice daily in children under age 6. 

Teniposide, a topoisomerase II inhibitor, is administered as an infusion over 30 to 60 minutes to prevent hypotension. The pharmacokinetics are described by a three-compartment model, with an a half-life of 0.75 hours, a (5 half-life of 4 hours, and a terminal half-life of 20 hours. Considerable variability in clearance of teniposide in children has been reported.17 Teniposide has shown activity in the treatment of acute lymphocytic leukemia, neuroblastoma, and non-Hodgkin s lymphoma. Side effects include myelosuppression, nausea, vomiting, mucositis, and venous irritation. Hypersensitivity reactions may be life-threatening. 

Children s Susceptibility. No studies were located in which comparisons were made between the sensitivity of children and adults to the toxicity of americium. Animal studies indicate that juvenile dogs are less susceptible than adults to americium-induced bone cancer (Lloyd et al. 1999). No direct evidence was located to indicate that the pharmacokinetics of americium in children may be different from that in adults. Based on dosimetric considerations related to differences in the parameters of available models, as well as studies in animals, it seems likely that children may be more susceptible to americium toxicity than are adults by virtue of age-related differences in pharmacokinetics. Absorption of ingested americium may be as much as 200 times greater in neonatal animals than in adults. (Bomford and Harrison 1986 David and Harrison 1984 Sullivan et al. 1985). 

C. Comaggia, S. Gianetti, D. Battino, T. Granato, A. Romeo, F. Viani, and G. Limido, Comparative pharmacokinetic study of chewable and conventional carbamazepine in children, Epilepsia, 34, 158 (1993). 

J. Bradley, L. Compogiannis, W. Murray, M. Acasta, and G. Tsu, Pharmacokinetics and safety of intramuscular injection of concentrated ceftriaxone in children, Clin. Pharmacol., 11, 961 (1992). 

P-gp is responsible for transport of the carboxylate form of irinotecan (64). The homozygous mutant 8 polymorphism has been associated with significantly increased exposure to irinotecan and its active metabolite SN-38 (65). Furthermore, significantly decreased docetaxel clearance was found in patients homozygous mutant for P-gp 8 (66), although Goh et al. (67) did not find a significant effect of this polymorphism on docetaxel pharmacokinetics. Also, a trend to an increased AUC of tipifamib in patients with the homozygous mutant allele compared to patients with only one or no mutant alleles of 8 was found in a study by Sparreboom et al. (68). In a study by Kishi et al. (40), the mutant allele for 6 was also correlated with a lower clearance of etoposide in children with ALL. 

Although there is no reason to suspect that the pharmacokinetics of 1,4-dichlorobenzene differs in children and adults, scant data are available to support or disprove this statement. Studies of absorption, distribution, metabolism, and excretion in children would aid in determining if children are at an increased risk, particularly if conducted in an area where a high-dose acute or low-dose chronic exposure to an environmental source were to occur. With regard to exposure during development, additional research on maternal and fetal/neonatal toxicokinetics, placental biotransformation, the mechanism of... 

---