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Comparison of sprinkle versus syrup formulations of valproate for bioavailability, tolerance, and preference
Comparison of sprinkle versus syrup formulations of valproate for bioavailability, tolerance, and preference J a m e s C. C l o y d , PharmD, Robert L. Kriel, MD, C a r o l y n M. J o n e s - S a e t e , RN, Betty Y. O n g , MD, Jon T. Jancik, BS, a n d Rory P. Remmel, PhD From the College of Pharmacy, University of Minnesota, Minneapolis, the Department of Neurology, Hennepin County Medical Center, Minneapolis, and Gillette Children's Hospital, St. Paul, Minnesota We c o m p a r e d a new coated-particle formulation of valproate (Depakote Sprinkle) capsules with valproic a c i d ( D e p a k e n e ) syrup for bioavailability, side effects, and patient and parent preference. Twelve children with epilepsy, a g e d 5 to 16 years, participated in this randomized, two-period, crossover study. They were assigned to a 7-day regimen with o n e formulation and then crossed over to the other; the drug was given every 12 hours. On d a y 7, b l o o d samples collected during a 12-hour period were analyzed for the presence of valproate. At the study's end, parents and children were asked structured questions regarding formulation preference and adverse events. The extent of absorption from sprinkle e q u a l e d that from syrup (relative bioavailability = 1.02), but absorption was slower (time to maximum concentration = 4.2 vs 0.9 hour; p <0.01). Fluctuations in serum concentrations were less with sprinkle (34.8% vs 62.3%; p <0.01). Sprinkle was preferred by 9 of the 12 parents b e c a u s e of ease of administration, and by nine of the children b e c a u s e of improved palatability. We c o n c l u d e that sprinkle may be substituted for syrup without c h a n g i n g the daily dose. Furthermore, sprinkle, b e c a u s e of its p r o l o n g e d absorption, may be given every 12 hours to children receiving monotherapy. C o m p l i a n c e may be e n h a n c e d b e c a u s e of the more convenient dosing schedules and the high d e g r e e of patient and parent a c c e p t a n c e . (J PED!ATR1992;120:634-8)
Valproic acid is an antiepileptic drug frequently prescribed to control seizure disorders in both children and adults. However, the syrup has an unpleasant taste and occasionally causes gastrointestinal distress, as does the capsule.l, 2 Rapid absorption of the syrup contributes to marked fluctuations in serum valproate concentrations. Although the
enteric-coated formulation reduces the frequency of gastrointestinal complaints, it does not lessen fluctuations in serum concentrations, a, 3 As a result, some clinicians recommend giving valproate three or four times daily. 4 We AUC Cma x
Supported in part by a grant from Abbott Laboratories. Presented in part at the annual meeting of the American Epilepsy Society, Baltimore, Md., Dec. 7, 1987. Submitted for publication July 31, 1991; accepted Nov. 19, 199 l. Reprint requests: James C. Cloyd, PharmD, HSUF--7115, College of Pharmacy, University of Minnesota, 308 Harvard St., Minneapolis, MN 55455. 9/25/35164
634
Cmin
Tmax
Area under the curve Maximum plasma concentration Minimum plasma concentration Time to achieve maximum concentration
designed this study to compare the bioavailability, clinical tolerance, and acceptance of a new formulation, divalproex sodium-coated particles in pull-apart capsules (Depakote Sprinkle), with that of valproic acid syrup (Depakene) in children receiving monotherapy.
Volume 120 Number 4, Part 1
Sprinkle vs syrup formulations o f valproate
635
Table I. Medical history and dosing data for 12 patients taking valproate sprinkle and syrup formulations Patient No.
Age (yr)
1 2 3 4 5 6 7 8 9 10 11 12
15.1 16.4 11.6 7.0 6.4 12.8 5.3 10.6 9.7 2.1 12.6 5.5
Phase I Syrup
Dose (mg)
Sprinkle
X X X X • X X X X X X X
AM
PM
Vaiproate monotherapy (yr)
500 500 125 250 125 250 125 500 250 250 625 125
500 500 250 250 125 500 250 500 250 250 625 125
3.8 1.3 1.8 0.7 2.2 3.3 2.1 0.5 0.9 2.3 0.7 1.1
Seizure type
Generalized tonic-clonic Complex partial Generalized tonic-clonic Generalized tonic-clonic Atypical absence Generalized tonie-clonic Generalized tonic-clonic/absence Generalized tonic-clonic Absence Generalized tonic-clonic Generalized tonic-clonic Generalized tonic-clonic/ absence/akinesla
METHODS Patients. Six boys and six girls, aged 5 to 16 years, participated in the study. All were in good general health except for their epilepsy, were receiving valproate monotherapy, and had had no seizures for the previous 6 months. Informed consent was obtained from the accompanying parent and, when appropriate, from the child after the purposes and procedures of the study had been explained. The protocol was approved by the Gillette Children's Hospital Institutional Review Board. Study design. The study was a randomized, two-period, crossover trial. In period 1, each child was assigned to a 7-day regimen in which either sprinkle or syrup was administered; in period 2 the alternative formulation was given. If children had been receiving syrup more than twice daily before the study, their regimens were changed to every 12 hours so that pharmacokinetic comparisons could be made between the two formulations. Equal morning and evening doses were given to 9 of the 12 children. Three children required unequal doses to accommodate the 125 mg capsules (Table I); the smaller dose was given in the morning. On day 7 of each period, each child was brought to our research center after an overnight fast. An indwelling intravenous catheter with a heparin lock was placed in the child's forearm. After catheter placement, the morning dose of valproate was administered. Sprinkle capsules were opened and the contents mixed with one or two tablespoons of applesauce; syrup was given with a glass of water. About 30 minutes later, the children were given a full breakfast consisting of cold cereal with milk, fruit juice, and toast; 4 hours later they had lunch, which consisted of a cold meat sandwich, fruit, cookies, and milk. They left the study site for the evening meal. Parents and children were followed for 8 weeks after the study to assess the development of side effects.
Sampling. Blood samples were collected just before the morning dose and 30 minutes and 1, 2, 4, 6, 8, and 12 hours afterward. Blood was drawn into Vacutainer tubes contain2 ing ethylenediaminetetraacetic acid, and centrifuged; the plasma was transferred and frozen at - 2 0 ~ C until analysis. Questionnaire. On day 7 of period 2, just before placement of the indwelling catheter, parents and children were questioned about their preferences regarding both formulations. The questions were structured and read verbatim by the same investigator in all cases. When drug samples were held up for demonstration, both were shown at the same time. At the time of enrollment, parents and children were informed that, if they wanted the sprinkle formulation after the study, it would be provided at no cost until it became commercially available. Sample analysis. Valproate concentrations in plasma were assayed by capillary gas chromatography. Duplicate standard curves were constructed with concentrations ranging from 1 to 200 mg/L. Samples from each patient were analyzed in duplicate, and all samples from an individual patient were processed on the same day. The between-days coefficients of variation were equal to or less than 5% at all concentrations. Pharmaeokinetic and statistical analyses. Maximum and minimum plasma concentrations during the dosing interval and time to achieve maximum concentration were determined by inspection of the data. The area under the plasma valproate concentration-time curve was calculated by the trapezoidal method. 5 The mean concentration (Cmean) was calculated by dividing a patient's morning dose by the resuiting 12-hour AUC. The relative bioavailability (Fret) of the sprinkle versus the syrup formulation was obtained from the following formula:
636
Cloyd et al.
The Journal of Pediatrics April 1992
140-
120-
~lO0g
_
~c" 80CO r cO
o 60 2
_~ 40-
9 Depakote sprinkle o Depakenesyrup
20-
o.s
T i m e (hours)
Figure. Mean plasma concentrations of valproate in 12 children immediately before administration of the morning dose of valproate and at regular intervals during the next 12 hours. The 12-hour samples were drawn after the evening meal (sprinkle = 0; syrup = O). Bars represent 1 SD.
AUC sprinkle 0 to 12 hr Fret = AUC syrup 0 to 12 hr The fluctuation index (Fi) between Cm~x and Cmin of valproate was determined with the following formula6:
ei
(Cmax -- Cmin) x 100 -
C ....
The measurements of bioavailability (AUC, Tmax, Cmax) were evaluated statistically by the method of Hills and A r m i t a g e 7 to determine whether any of the differences between the formulations were due to a period effect associated with the sequence of administration. Subsequently a Student t test for paired samples was used to assess the differences in mean values measuring absorption of the two formulations. A p value of --<0.05 was considered significant. Data from the questionnaires were tabulated and reported as ratios. RESULTS The sprinkle formulation produced a significantly later Tmax, lower Cmax, and higher Cmin (Figure). Mean pharmacokinetic and bioavailability data" derived from the plasma concentration-time curves for both formulations are shown in Table II. The amount of valproate absorbed from the sprinkle preparation was equal to that from syrup
( F = 1.02; p = 0.206).* Valproate bioavailability from the sprinkle formulation was within + 6% of that for the syrup formulation in 10 of the 12 children. In the remaining two, absorption from sprinkle was 12% and 18%, respectively, greater than that from syrup. Tmax occurred 4 hours after sprinkle administration in all but one child, whose Tmax was 6 hours. In comparison, Tmax after administration of syrup was distributed as follows: 30 minutes in five children, 1 hour in six children, and 2 hours in one child. When children and parents were questioned regarding their formulation preferences, nine parents chose the sprinkle because it was easier to administer; two also said that it allowed their children to self-medicate. Nine children found the sprinkle more palatable than the syrup; the other three had no preference. N o side effects or seizures were reported during the study. Eleven families continued use of the sprinkle preparation during the 8-week follow-up period. During this time, one child had gastrointestinal distress, discontinued therapy with the sprinkle formulation, and resumed the use of divalproex sodium enteric-coated tablets; the problem did not recur. Another child had a seizure during the follow-up period. DISCUSSION Our results demonstrate that valproate absorption from a sprinkle formulation equals that from syrup, but Tmax and the fluctuation index differ significantly. There was minimal interpatient variation in sprinkle bioavailability; for 10 of the 12 children, the relative bioavailability of drug in the sprinkle preparation (_+ 6%) approximated laboratory error. In the other two children, valproate bioavailability from sprinkle was greater but remained within U.S. Food and Drug Administration guidelines. 9 The consistency in sprinkle bioavailability means that most children switching from valproate syrup to sprinkle can be given the same daily dose without risk of complications. However, flexibility in individualizing dosage is limited, because the sprinkle preparation is available only in a fixed dose (125 rag). The Tm~x was significantly later with sprinkle, indicating prolonged absorption. T~,x is governed by the rates of both absorption and elimination. 5 Valproate elimination rates remained essentially unchanged because in this crossover study each child received both formulations within 1 week. Thus the difference in Tmax is best explained by a slower rate of absorption after sprinkle administration. Carrigan et *A significant period effect was detected: syrup AUCs in period 1 were about 17% greater than those for sprinkle; the oppositewas true in period 2. Children receivingsyrup in period 1 had the same dose (in milligramsper kilogram) as children receivingsprinkle (7.0 vs 7.2 mg) but wereolder (12.1 vs 9.5 years). We attributed the period effect to age difference;valproate clearances aregreater in younger children than in older children or adults; thus AUCs are smaller in younger than in older children given the same dose.8 We concludedthat the period effectwas not due to a formulationdifference; thus the pooling of data from both periods was justified.
Volume 120 Number 4, Part 1
Sprinkle vs syrup formulations o f valproate
637
T a b l e II. Absorption characteristics of valproate in two formulations: sprinkle versus syrup
Formulation Sprinkle Syrup
Tmax (hr)
Cmax (rag/L)
Cmin (mg/L)
AUC (mg. hr/L)
Fluctuation index (%)
4.2 +_ 0.6 0.9 _+ 0.4
88.8 + 19.5 100.7 + 21.2
62.4 _+ 15.7 54.3 + 14.2
923.9 + 208.7 902.1 + 212.0
34.8 + 0.1 62.3 + 0.1
F 1.02
All values for sprinkle versus syrup were significant at the p <0.01 level except those for A U C and F. Values are expressed as mean + SD. F, Bioavailability.
al. l~ invoked the same explanation to account for the later Tmax after the administration of sprinkle than after the administration of enteric-coated divalproex sodium tablets as observed in healthy volunteers given both formulations. For each child, plasma valproate concentrations after administration of the sprinkle formulation fluctuated less than those for syrup. The greater fluctuation index for valPr0ate syrup is explained by its rapid absorption, and was exaggerated by the use of a 12-hour dosing interval. Large fluctuations in valproate concentrations after administration of syrup can be minimized by more frequent dosing, which is the reason that many clinicians recommend that the syrup be given three or four times a day. However, Cramer et a1.11 showed that such regimens increase the risk of noncompliance. The difference in Tmaxsuggests that valproate absorption from the sprinkle preparation is slower than that from syrup, producing less fluctuation between peak and trough plasma concentrations. We infer that most children 5 years of age or older who are receiving valproate monotherapy can be given the sprinkle formulation every 12 hours. In a previous pharmacokinetic study involving 11 children receiving valproate monotherapy, we found that the elimination half-life exceeded 12 hours in five children.12 Such patients may be able to take valproate sprinkle once a day, with a fluctuation index of 50% or less. We recommend that steady-state, trough valproate concentrations be measured to ensure that desired plasma concentrations are attained. Food slows the Tmax of valproate in syrup or capsule but does not reduce the amount of drug absorbed} Valproate in enteric-coated capsules has a delayed onset of absorption, but once the tablet disintegrates, the drug is quickly and completely absorbed. 3, 13 In a study of the effect of food on valproate bioavailabilityin 11 healthy volunteers taking divalproex sodium sprinkle under fasting and nonfasting conditions, Carrigan et alJ ~ found that the ingestion of food resulted in a significantlylater mean Tmax (4.6 vs 3.7 hours) but did not alter bioavailability. The children in our study took the sprinkle preparation with 1 to 2 tablespoons of applesauce, and then had breakfast at least 30 minutes later. The mean Tmax in our study was intermediate between the fasting and nonfasting values observed in adults. Additional studies are needed to determine whether food will affect either Tmax or the amount of drug absorbed by children.
Most children and parents in our study preferred the sprinkle formulation. However, they may have been biased by the knowledge that it would be provided gratis when the study was over. The sprinkle formulation has little or no taste, but it does have a gritty texture, although none of the children objected to it. Parents liked the pull-apart feature of the sprinkle capsules because it made administration easier. Some parents commented that it allowed their children to self-medicate, giving them a greater sense of control over their treatment; the parents believed that this would enhance children's compliance. The sprinkle formulation may produce less nausea; theoretically the coated particles should minimize local irritation, and the slower absorption rate could reduce centrally mediated nausea} Nevertheless, one child complained of stomach upset during the follow-up study and was switched to enteric-coated tablets. Valproic acid is a gastrointestinal irritant; formulations such as the enteric-coated tablet and the sprinkle capsule may reduce but not completely eliminate this problem. Another child had a seizure during the follow-up period; there was no apparent cause, nor were valproate concentrations measured at the time of the seizure. Possibly the seizure resulted from subtherapeutic valproate concentrations, but the occurrence of a single seizure in a child with epilepsy is not unusual. Occasionally, residual coated particles ("ghosts") were detected in the stools of patients in the study. In our clinical practice, the majority of parents whose children are taking the sprinkle capsule report that they occasionally find valproate ghosts. A minority of children have ghosts in almost all stools. In our experience the appearance of ghosts does not seem to decrease valproate concentration nor alter seizure control. However, we recommend that valproate concentrations be periodically measured in children when ghosts are frequently observed. We conclude that the amount of valproate absorbed from the sprinkle formulation is equal to that from syrup. Although the availability of a single-strength, fixed-dose capsule limits individualization of dosage, the sprinkle capsule appears to possess several advantages, including prolonged absorption, less peak-to-trough fluctuation in plasma valproate concentrations, and ease of administration. These advantages should enhance patient compliance with therapy.
638
Cloyd et al.
REFERENCES
1. Henriksen O, Johannessen SI. Clinical and pharmacokinetic observations on sodium valproate: a five-year follow-up study of 100 children with epilepsy. Acta Neurol Scand 1982;65:50423. 2. Wilder BJ, Karas BJ, Penry JK, Asconape J. Gastrointestinal tolerance of divalproex sodium. Neurology t983;33:808-11. 3. Fischer JH, Barr AN, Paloucek FP, Doroeiak JV, Spunt AL. Effect of food on the serum concentration profile of entericcoated valproic acid. Neurology 1988;38:1319-22. 4. Acardi J. Epilepsy in children. New York: Raven Press, 1986:319-40. 5. Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York: Marcel Dekker, 1982:445-50. 6. Eeg-Olofsson O, Nilsson HL, Tonnby B, et al. Diurnal variation of carbamazepine and carbamazepine-10, 1l-epoxide in plasma and saliva in children with epilepsy: a comparison between conventional and slow-release formulations. J Child Neurol 1990;56:159-65. 7. Hills M, Armitage P. The two-period cross-over clinical trial. Br J Clin Pharmacol 1979;8:7-20.
The Journal of Pediatrics April 1992
8. Dodson WE, Tasch V. Pharmacology of valproic acid in children with severe epilepsy: clearance and hepatotoxicity. Neurology 1981;31:1047-50. 9. Rheinstein P. Report of the Bioequivalenee Task Force on Recommendations from the Bioequivalence Hearing Conducted by the Food and Drug Administration. Washington, D.C.: Food and Drug Administration, 1988. 10. Carrigan PJ, Brinker DR, Cavanaugh JH, Lamm JE, Cloyd JC. Absorption characteristics of a new valproate formulation: divalproex sodium-coated particles in capsules (Depakote Sprinkle). J Clin Pharmacol 1990;30:743-7. 11. Cramer JA, Mattson RH, Prevey ML, Scheyer RD, Ouellette VL. How often is medication taken as prescribed? JAMA 1989;261:3273-7. 12. Cloyd JC, Kriel RL, Fischer JH. Valproic acid pharmacokinetics in children. II. Discontinuation of concomitant antiepileptic drug therapy. Neurology 1985;35:1623-7. 13. Chun AHC, Hoffman D J, Friedmann N, Carrigan PJ. Bioavailability of valproic acid under fasting/nonfasting regimens. J Clin Pharmacol 1980;20:30-6.
Clinical and laboratory observations Pathogenesis of cyclosporine-induced hypomagnesemia Tomio Nozue, MD, Akio Kobayashi, MD, Takehisa Kodama, PhD, Fujio Uemasu, MD, Hiroomi Endoh, MD, Akiko Sako, MD, and Yasuo Takagi, MD From the Department of Pediatrics, Showa University Toyosu Hospital, Tokyo, and the Research and Development Division, Shimizu Pharmaceutical Co. Ltd., Shimizu, Japan
We studied the pathogenesis of cyclosporine-induced hypomagnesemia in five patients with nephrosis. Serum magnesium concentrations and urinary excretion of magnesium were reduced by the therapy. In contrast, the magnesium concentrations in mononuclear blood cells were increased. We conclude that short-term use of cyclosporine induces an intracellular shift of magnesium and causes hypomagnesemia. (J PEDIATR1992;120:638-40)
Submitted for publication July 29, 1991; accepted Nov. 6, 1991.Reprint requests: T. Nozue, MD, Department of Pediatrics, Showa University Toyosu Hospital, Koto-ku, Toyosu, 4-1-18, Tokyo, 135, Japan. 9/26/34849
Hypomagnesemia, frequently encountered in patients treated with eyclosporine, l3 may be associated with neurologic symptoms, such as seizure, cerebellar ataxia, and tremor, 4 and with the development of hypertension. 5 Inappropriately elevated excretion and fractional excretion of
Valproic acid is an antiepileptic drug frequently prescribed to control seizure disorders in both children and adults. However, the syrup has an unpleasant taste and occasionally causes gastrointestinal distress, as does the capsule.l, 2 Rapid absorption of the syrup contributes to marked fluctuations in serum valproate concentrations. Although the
enteric-coated formulation reduces the frequency of gastrointestinal complaints, it does not lessen fluctuations in serum concentrations, a, 3 As a result, some clinicians recommend giving valproate three or four times daily. 4 We AUC Cma x
Supported in part by a grant from Abbott Laboratories. Presented in part at the annual meeting of the American Epilepsy Society, Baltimore, Md., Dec. 7, 1987. Submitted for publication July 31, 1991; accepted Nov. 19, 199 l. Reprint requests: James C. Cloyd, PharmD, HSUF--7115, College of Pharmacy, University of Minnesota, 308 Harvard St., Minneapolis, MN 55455. 9/25/35164
634
Cmin
Tmax
Area under the curve Maximum plasma concentration Minimum plasma concentration Time to achieve maximum concentration
designed this study to compare the bioavailability, clinical tolerance, and acceptance of a new formulation, divalproex sodium-coated particles in pull-apart capsules (Depakote Sprinkle), with that of valproic acid syrup (Depakene) in children receiving monotherapy.
Volume 120 Number 4, Part 1
Sprinkle vs syrup formulations o f valproate
635
Table I. Medical history and dosing data for 12 patients taking valproate sprinkle and syrup formulations Patient No.
Age (yr)
1 2 3 4 5 6 7 8 9 10 11 12
15.1 16.4 11.6 7.0 6.4 12.8 5.3 10.6 9.7 2.1 12.6 5.5
Phase I Syrup
Dose (mg)
Sprinkle
X X X X • X X X X X X X
AM
PM
Vaiproate monotherapy (yr)
500 500 125 250 125 250 125 500 250 250 625 125
500 500 250 250 125 500 250 500 250 250 625 125
3.8 1.3 1.8 0.7 2.2 3.3 2.1 0.5 0.9 2.3 0.7 1.1
Seizure type
Generalized tonic-clonic Complex partial Generalized tonic-clonic Generalized tonic-clonic Atypical absence Generalized tonie-clonic Generalized tonic-clonic/absence Generalized tonic-clonic Absence Generalized tonic-clonic Generalized tonic-clonic Generalized tonic-clonic/ absence/akinesla
METHODS Patients. Six boys and six girls, aged 5 to 16 years, participated in the study. All were in good general health except for their epilepsy, were receiving valproate monotherapy, and had had no seizures for the previous 6 months. Informed consent was obtained from the accompanying parent and, when appropriate, from the child after the purposes and procedures of the study had been explained. The protocol was approved by the Gillette Children's Hospital Institutional Review Board. Study design. The study was a randomized, two-period, crossover trial. In period 1, each child was assigned to a 7-day regimen in which either sprinkle or syrup was administered; in period 2 the alternative formulation was given. If children had been receiving syrup more than twice daily before the study, their regimens were changed to every 12 hours so that pharmacokinetic comparisons could be made between the two formulations. Equal morning and evening doses were given to 9 of the 12 children. Three children required unequal doses to accommodate the 125 mg capsules (Table I); the smaller dose was given in the morning. On day 7 of each period, each child was brought to our research center after an overnight fast. An indwelling intravenous catheter with a heparin lock was placed in the child's forearm. After catheter placement, the morning dose of valproate was administered. Sprinkle capsules were opened and the contents mixed with one or two tablespoons of applesauce; syrup was given with a glass of water. About 30 minutes later, the children were given a full breakfast consisting of cold cereal with milk, fruit juice, and toast; 4 hours later they had lunch, which consisted of a cold meat sandwich, fruit, cookies, and milk. They left the study site for the evening meal. Parents and children were followed for 8 weeks after the study to assess the development of side effects.
Sampling. Blood samples were collected just before the morning dose and 30 minutes and 1, 2, 4, 6, 8, and 12 hours afterward. Blood was drawn into Vacutainer tubes contain2 ing ethylenediaminetetraacetic acid, and centrifuged; the plasma was transferred and frozen at - 2 0 ~ C until analysis. Questionnaire. On day 7 of period 2, just before placement of the indwelling catheter, parents and children were questioned about their preferences regarding both formulations. The questions were structured and read verbatim by the same investigator in all cases. When drug samples were held up for demonstration, both were shown at the same time. At the time of enrollment, parents and children were informed that, if they wanted the sprinkle formulation after the study, it would be provided at no cost until it became commercially available. Sample analysis. Valproate concentrations in plasma were assayed by capillary gas chromatography. Duplicate standard curves were constructed with concentrations ranging from 1 to 200 mg/L. Samples from each patient were analyzed in duplicate, and all samples from an individual patient were processed on the same day. The between-days coefficients of variation were equal to or less than 5% at all concentrations. Pharmaeokinetic and statistical analyses. Maximum and minimum plasma concentrations during the dosing interval and time to achieve maximum concentration were determined by inspection of the data. The area under the plasma valproate concentration-time curve was calculated by the trapezoidal method. 5 The mean concentration (Cmean) was calculated by dividing a patient's morning dose by the resuiting 12-hour AUC. The relative bioavailability (Fret) of the sprinkle versus the syrup formulation was obtained from the following formula:
636
Cloyd et al.
The Journal of Pediatrics April 1992
140-
120-
~lO0g
_
~c" 80CO r cO
o 60 2
_~ 40-
9 Depakote sprinkle o Depakenesyrup
20-
o.s
T i m e (hours)
Figure. Mean plasma concentrations of valproate in 12 children immediately before administration of the morning dose of valproate and at regular intervals during the next 12 hours. The 12-hour samples were drawn after the evening meal (sprinkle = 0; syrup = O). Bars represent 1 SD.
AUC sprinkle 0 to 12 hr Fret = AUC syrup 0 to 12 hr The fluctuation index (Fi) between Cm~x and Cmin of valproate was determined with the following formula6:
ei
(Cmax -- Cmin) x 100 -
C ....
The measurements of bioavailability (AUC, Tmax, Cmax) were evaluated statistically by the method of Hills and A r m i t a g e 7 to determine whether any of the differences between the formulations were due to a period effect associated with the sequence of administration. Subsequently a Student t test for paired samples was used to assess the differences in mean values measuring absorption of the two formulations. A p value of --<0.05 was considered significant. Data from the questionnaires were tabulated and reported as ratios. RESULTS The sprinkle formulation produced a significantly later Tmax, lower Cmax, and higher Cmin (Figure). Mean pharmacokinetic and bioavailability data" derived from the plasma concentration-time curves for both formulations are shown in Table II. The amount of valproate absorbed from the sprinkle preparation was equal to that from syrup
( F = 1.02; p = 0.206).* Valproate bioavailability from the sprinkle formulation was within + 6% of that for the syrup formulation in 10 of the 12 children. In the remaining two, absorption from sprinkle was 12% and 18%, respectively, greater than that from syrup. Tmax occurred 4 hours after sprinkle administration in all but one child, whose Tmax was 6 hours. In comparison, Tmax after administration of syrup was distributed as follows: 30 minutes in five children, 1 hour in six children, and 2 hours in one child. When children and parents were questioned regarding their formulation preferences, nine parents chose the sprinkle because it was easier to administer; two also said that it allowed their children to self-medicate. Nine children found the sprinkle more palatable than the syrup; the other three had no preference. N o side effects or seizures were reported during the study. Eleven families continued use of the sprinkle preparation during the 8-week follow-up period. During this time, one child had gastrointestinal distress, discontinued therapy with the sprinkle formulation, and resumed the use of divalproex sodium enteric-coated tablets; the problem did not recur. Another child had a seizure during the follow-up period. DISCUSSION Our results demonstrate that valproate absorption from a sprinkle formulation equals that from syrup, but Tmax and the fluctuation index differ significantly. There was minimal interpatient variation in sprinkle bioavailability; for 10 of the 12 children, the relative bioavailability of drug in the sprinkle preparation (_+ 6%) approximated laboratory error. In the other two children, valproate bioavailability from sprinkle was greater but remained within U.S. Food and Drug Administration guidelines. 9 The consistency in sprinkle bioavailability means that most children switching from valproate syrup to sprinkle can be given the same daily dose without risk of complications. However, flexibility in individualizing dosage is limited, because the sprinkle preparation is available only in a fixed dose (125 rag). The Tm~x was significantly later with sprinkle, indicating prolonged absorption. T~,x is governed by the rates of both absorption and elimination. 5 Valproate elimination rates remained essentially unchanged because in this crossover study each child received both formulations within 1 week. Thus the difference in Tmax is best explained by a slower rate of absorption after sprinkle administration. Carrigan et *A significant period effect was detected: syrup AUCs in period 1 were about 17% greater than those for sprinkle; the oppositewas true in period 2. Children receivingsyrup in period 1 had the same dose (in milligramsper kilogram) as children receivingsprinkle (7.0 vs 7.2 mg) but wereolder (12.1 vs 9.5 years). We attributed the period effect to age difference;valproate clearances aregreater in younger children than in older children or adults; thus AUCs are smaller in younger than in older children given the same dose.8 We concludedthat the period effectwas not due to a formulationdifference; thus the pooling of data from both periods was justified.
Volume 120 Number 4, Part 1
Sprinkle vs syrup formulations o f valproate
637
T a b l e II. Absorption characteristics of valproate in two formulations: sprinkle versus syrup
Formulation Sprinkle Syrup
Tmax (hr)
Cmax (rag/L)
Cmin (mg/L)
AUC (mg. hr/L)
Fluctuation index (%)
4.2 +_ 0.6 0.9 _+ 0.4
88.8 + 19.5 100.7 + 21.2
62.4 _+ 15.7 54.3 + 14.2
923.9 + 208.7 902.1 + 212.0
34.8 + 0.1 62.3 + 0.1
F 1.02
All values for sprinkle versus syrup were significant at the p <0.01 level except those for A U C and F. Values are expressed as mean + SD. F, Bioavailability.
al. l~ invoked the same explanation to account for the later Tmax after the administration of sprinkle than after the administration of enteric-coated divalproex sodium tablets as observed in healthy volunteers given both formulations. For each child, plasma valproate concentrations after administration of the sprinkle formulation fluctuated less than those for syrup. The greater fluctuation index for valPr0ate syrup is explained by its rapid absorption, and was exaggerated by the use of a 12-hour dosing interval. Large fluctuations in valproate concentrations after administration of syrup can be minimized by more frequent dosing, which is the reason that many clinicians recommend that the syrup be given three or four times a day. However, Cramer et a1.11 showed that such regimens increase the risk of noncompliance. The difference in Tmaxsuggests that valproate absorption from the sprinkle preparation is slower than that from syrup, producing less fluctuation between peak and trough plasma concentrations. We infer that most children 5 years of age or older who are receiving valproate monotherapy can be given the sprinkle formulation every 12 hours. In a previous pharmacokinetic study involving 11 children receiving valproate monotherapy, we found that the elimination half-life exceeded 12 hours in five children.12 Such patients may be able to take valproate sprinkle once a day, with a fluctuation index of 50% or less. We recommend that steady-state, trough valproate concentrations be measured to ensure that desired plasma concentrations are attained. Food slows the Tmax of valproate in syrup or capsule but does not reduce the amount of drug absorbed} Valproate in enteric-coated capsules has a delayed onset of absorption, but once the tablet disintegrates, the drug is quickly and completely absorbed. 3, 13 In a study of the effect of food on valproate bioavailabilityin 11 healthy volunteers taking divalproex sodium sprinkle under fasting and nonfasting conditions, Carrigan et alJ ~ found that the ingestion of food resulted in a significantlylater mean Tmax (4.6 vs 3.7 hours) but did not alter bioavailability. The children in our study took the sprinkle preparation with 1 to 2 tablespoons of applesauce, and then had breakfast at least 30 minutes later. The mean Tmax in our study was intermediate between the fasting and nonfasting values observed in adults. Additional studies are needed to determine whether food will affect either Tmax or the amount of drug absorbed by children.
Most children and parents in our study preferred the sprinkle formulation. However, they may have been biased by the knowledge that it would be provided gratis when the study was over. The sprinkle formulation has little or no taste, but it does have a gritty texture, although none of the children objected to it. Parents liked the pull-apart feature of the sprinkle capsules because it made administration easier. Some parents commented that it allowed their children to self-medicate, giving them a greater sense of control over their treatment; the parents believed that this would enhance children's compliance. The sprinkle formulation may produce less nausea; theoretically the coated particles should minimize local irritation, and the slower absorption rate could reduce centrally mediated nausea} Nevertheless, one child complained of stomach upset during the follow-up study and was switched to enteric-coated tablets. Valproic acid is a gastrointestinal irritant; formulations such as the enteric-coated tablet and the sprinkle capsule may reduce but not completely eliminate this problem. Another child had a seizure during the follow-up period; there was no apparent cause, nor were valproate concentrations measured at the time of the seizure. Possibly the seizure resulted from subtherapeutic valproate concentrations, but the occurrence of a single seizure in a child with epilepsy is not unusual. Occasionally, residual coated particles ("ghosts") were detected in the stools of patients in the study. In our clinical practice, the majority of parents whose children are taking the sprinkle capsule report that they occasionally find valproate ghosts. A minority of children have ghosts in almost all stools. In our experience the appearance of ghosts does not seem to decrease valproate concentration nor alter seizure control. However, we recommend that valproate concentrations be periodically measured in children when ghosts are frequently observed. We conclude that the amount of valproate absorbed from the sprinkle formulation is equal to that from syrup. Although the availability of a single-strength, fixed-dose capsule limits individualization of dosage, the sprinkle capsule appears to possess several advantages, including prolonged absorption, less peak-to-trough fluctuation in plasma valproate concentrations, and ease of administration. These advantages should enhance patient compliance with therapy.
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Cloyd et al.
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The Journal of Pediatrics April 1992
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Clinical and laboratory observations Pathogenesis of cyclosporine-induced hypomagnesemia Tomio Nozue, MD, Akio Kobayashi, MD, Takehisa Kodama, PhD, Fujio Uemasu, MD, Hiroomi Endoh, MD, Akiko Sako, MD, and Yasuo Takagi, MD From the Department of Pediatrics, Showa University Toyosu Hospital, Tokyo, and the Research and Development Division, Shimizu Pharmaceutical Co. Ltd., Shimizu, Japan
We studied the pathogenesis of cyclosporine-induced hypomagnesemia in five patients with nephrosis. Serum magnesium concentrations and urinary excretion of magnesium were reduced by the therapy. In contrast, the magnesium concentrations in mononuclear blood cells were increased. We conclude that short-term use of cyclosporine induces an intracellular shift of magnesium and causes hypomagnesemia. (J PEDIATR1992;120:638-40)
Submitted for publication July 29, 1991; accepted Nov. 6, 1991.Reprint requests: T. Nozue, MD, Department of Pediatrics, Showa University Toyosu Hospital, Koto-ku, Toyosu, 4-1-18, Tokyo, 135, Japan. 9/26/34849
Hypomagnesemia, frequently encountered in patients treated with eyclosporine, l3 may be associated with neurologic symptoms, such as seizure, cerebellar ataxia, and tremor, 4 and with the development of hypertension. 5 Inappropriately elevated excretion and fractional excretion of