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Pharmacokinetics of quinine in children
Pharmacokinetics of quinine in children Serum quinine concentrations were measured in seven children after intravenous infusion of quinine dihydrochloride, in eight children after intramuscular injection of quinine dihydrochloride, and in six children after nasogastric administration of a solution of quinine dihydrochloride. The mean ( + SD) half-life of quinine was 11.1 +- 4.8 hours, and the volume of distribution was 139 +_ 0.37 L/kg. To attain a serum level of 10 l~g/ml quinine, we suggest that children with severe malaria be given a loading dose of 20 mg/kg qMninr dihydrochloride parenterally, followed by 7.5 mg/kg every 8 hours. Once recovery begins, quinine sulphate 10 mg/kg may be given orally:every 8 hours. Serum concentrations should be monitored, if possible, because they vary.greatly from person to person. Quinine is rapidly and completely absorbed after either intramuscular or nasogastric administration. (J PEDIATR 106:506; 1985)
Frank Shann, F.R.A.C.P, John Stace, M.B., B.S., and Michael Edstein, B.Sc. P a p u a N e w G u i n e a a n d Ingleburn, A u s t r a l i a
IN 1980-i981, 3316 cases of malaria were reported to the Centers for Disease Control--more than the total number of civilian cases reported in the previous 10 years. 1 The number of cases of chloroquine-resistant malaria treated in the United States is likely to increase: not only are more cases of malaria occurring, but it is probable that an increasing proportion will be insensitive to chloroquine as resistance spreads through the endemic areas of the world/ Quinine is the treatment of choice for severe chloroquineresistant falciparum malaria. 3 Although there have been some studies of the pharmacokinetics of quinine in adults, 47 very little Work has been done in children/ In the less developed countries, intravenous infusion of quinine is expensive, increases the risk of cerebral edema, and is unsuitable for use by primary health workers. Intramuscular administration of quinine does not have these disadvantages, but the drug is said to be poorly absorbed and to cause pain and tissue necrosis/' 9 However, intramuscular injections of quinine have been given for many years by medical workers in Papua New Guinea, and no serious problems have been observed, either with From the Departments of Pediatrics, Goroka Base Hospital, Madang Hospital, and the Army Malaria Research Unit. Submitted for publication March 14, 1984; accepted Aug. 13, 1984. Reprint requests: Frank Shann, F.R.A.C.P., Intensive Care Unit, Royal Children's Hospital, Parkville, Victoria 3052, Australia.
506
TheJournalofPEDIATRICS
routine clinical use or during a pilot study that was done preliminary to our investigation/~ We measured serum quinine levels in children after intravenous, intramuscular, and nasogastric administration of quinine dihydroehloride.
METHODS Malaria is endemic in the Madang area of Papua New Guinea, and chtoroquine-resistant Plasmodium falciparum is common." Cerebral malaria is diagnosed when the blood slide is positive for asexual forms of P. falciparum
M1C tVz Va
Minimum inhibitory concentration Half-life Volume of distribution
I I
I
and the patient is unarousable with no other demonstrable cause of unconsciousness. 7 However, in Madang all comatose children, including those with meningitis, are given quinine. Conscious children with falciparum malaria who do not improve with chloroquine therapy are also given quinine. All comatose children admitted to Madang Hospital between March and August 1982 were given quinine dihydrochloride either intravenously or intramuscularly. Allocation to intravenous or intramuscular treatment was not random; intravenous treatment was given only when the ward was not too busy. Quinine dihydrochloride was
Volume 106 Number 3
Pharmacokinetics o f quinine
507
Table I. Characteristics of children studied Quinine administration
Intravenous Intramuscular Nasogastric
Range
Maximum temperature (~C) (mean + SD)
Total serum biIirubin (~g/ml) (mean +_SD)
1 to 96 5 to 48 18 to 72
38.4 • 1.4 38.6 + 1.0 39.0 • 1.3
0.29 • 0.24 0.54 • 0.56 0.52 _+ 0.28
Age (too)
P. falciparum positive
Mean
3 of 7 6 of 8 4 of 6
33 30 41
given via nasogastric tube to all conscious children with malaria not responding to chtoroquine therapy. Verbal consent was obtained from the parent(s) of each child. The study was approved by the Papua New Guinea Medical Research Advisory Committee. The ages of the children studied ranged from 1 to 96 months (Table I). After a pilot study of quinine levels in children in Papua New Guinea, ~~it was decided to give a dose of 300 mg/m z quinine dihydrochloride (Rotexmedica 60 mg/ml, 57.1 mg/ml quinine base). In seven children, 300 mg/m 2 quinine dihydrochloride was infused dntravenously over 4 hours. Venous blood samples were taken from the opposite arm at 0, 2, 4, 6, and 12 hours, and in three children 24 hours, after the start of the infusion. Eight children were given 300 mg/m 2quinine dihydrochloride by deep intramuscular injection from a glass syringe, and venous blood samples were taken after 1, 2, 6, and 12 hours. Six of the eight children were restudied after having received 300 mg/m 2 quinine dihydrochloride intramuscularly every 12 hours for 5 days. The sites of injection were inspected daily for evidence of induration or abscess formation. In six children quinine dihydrochloride was administered by nasogastric tube; the parenteral solution was used rather than tablets. Blood samples were taken 0, 3, 6, 9, 12, and 18 hours after nasogastric administration. After collection, the blood was centrifuged and the serum stored at - 2 0 ~ C. Levels of quinine (base) were measured by high-performance liquid chromatography. Several aspects of the collection and storage of samples and the assay of quinine were studied; the details have been published elsewhere. ~2 For each child a thick and thin blood film was examined for malarial parasites. Table I shows the number of blood slides positive for P. falciparum. In one of the two children in the nasogastric quinine group, the blood film was negative for P. falciparum, but positive for P. vivax. In each child serum bilirubin was measured on admission and body temperature recorded every 4 hours. The elimination half-tile of quinine was calculated for each child individually from the terminal log-linear portion of the concentration-time curve by calculating the regres-
sion of the logarithm of the serum concentration of quinine against time by the least-squares method. To calculate the volume of distribution of quinine, the serum levels for each child were plotted On graph paper and the plot extended to 50 hours using the calculated half-life for that child. The area under the curve was determined by weighing. The volume of distribution was calculated from the formula V~ = (Dose • tl/2)/(AUC X 0.693) where the dose of quinine base was expressed in milligrams per kilogram, tlA was the half-life in hours, and AUC was the area under the serum concentration curve i n micrograms per milliliter per hour. RESULTS Serum quinine concentrations were measured in seven patients after intravenous infusion of quinine dihydrochloride, in eight patients after intramuscular injection, and in six patients after nasogastric administration (Table II and Fig. 1). In the three groups combined, the 300 mg/m 2 dose of quinine dihydrochloride averaged (mean _+ SD) 14.6 _+ 1.8 mg/kg (13.9 _+ 1.7 mg/kg base). After the end of the 4-hour intravenous infusion of quinine dihydrochloride, the logarithmic concentration of quinine declined in a linear fashion in all seven patients. The tF2 in this group was 12.47 _+ 4.01 hours, and Vd 1.51 + 0.39 L/kg. After intramuscular administration, quinine dihydrochloride was rapidly absorbed. The highest concentration was measured at 1 hour in five of the eight children studied, and at 2 hours in the other three (in one of these, no sample was taken at 1 hour) (Fig. 2). The logarithmic concentration of quinine declined in a linear fashion from 1 hour after intramuscular injection in five of the eight patients studied and from 2 hours after injection in the other three (in one of these, no sample was taken at 1 hour). The tV2 of-Nhinine in this group was 8.35 • 2.78 hours, and Vd 1.29 • L/kg. In six children, quinine dihydrochloride 300 mg/m 2 was given ]ntramuscularly every 12 hours, and serum levels of the drug were measured again on day 5. The mean serum quinine concentra-
508
Shann, Stace, and Edstein
The Journal of Pediatrics March 1985
12
8
Ir
"-Z'--..'."-..
.~
*"..
~
"* NASOGASTRIC
INTRAMUSCULAR
0
I
2.
I
I
4
6
j
8
"'...
I
1
'1
]
1
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~
1
10
12
14
16
18
20
22
24
HOURS Fig. 1. Mean serum concentrations of quinine after intravenous, intramuscular, and nasogastric administration.
Table IL S e r u m concentrations of quinine after intravenous, intramuscular, and nasogastric administration
Serum quinine (gg/ml Intravenous infusion
t89 (hr)
Vd (hr)
Hr 0 0.0 • 0.0 (7)
Hr 2 8.5 + 3.2 (6)
Hr 4 9.7 • 3.7 (7)
Hr 6 8.2_+ 3.2 (7)
Hr 12 5.8 • 3.1 (7)
Hr 24 3.1 _+ 0.9 (3)
12.5_+4.0
1.5 • 0.4
Hr 0 0.0 --4-0.0 (6)
Hr 1 10.6 • 4.4 (7)
Hr 2 10.0 • 4.0 (8)
Hr 6 7.4 • 3.5 (8)
Hr 12 4.3 • 2.5 (8)
--
8.4 + 2.8
1.3 _+ 0.3
Hr 0 0.0 • 0.0 (6)
Hr 3 10.3 + 5.7 (6)
Hr6 8.9 • 4.8 (6)
Hr9 8.6_+ 6.6 (4)
Hr 12 6.9_+ 4.9 (6)
Hr 18 5.2 • 4.8 (6)
13.1 _+ 6.5
].4_+ 0.5
(n = 7)
Intramuscular injection (n = 8)
Nasogastric administration (n = 6)
Values represent mean _+SD; number of children in parentheses.
tion was I 1.3 .+ 4.0 # g / m l 1 hour after the injection, and 6.5 _+ 4.6 # g / m l at 12 hours. T h e t 89 was 9.8 _+ 1.9 hours. After nasogastric administration of quinine dihydrochloride, the highest recorded serum concentration occurred at 3 hours in five of the six children studied and at 6 hours in one child (Fig. 2). Linear decline in the logarithmic concentration occurred after 3 hours in four of the six children and after 9 hours in one child. T h e m e a n t 89 in this group was 13.13 .+ 6.46 hours and the Vd was 1.38 _+ 0.48 L / k g .
T h e t 89 of quinine in the four children with cerebral malaria was 8.48 _ 2.56 hours, and Vd 1.44 _ 0.01 L / k g . In the nine conscious children with falciparum malaria, the t 89 of quinine was 10.82 _+ 4.69 hours, and Vd 1.33 _+ 0.37 L / k g . In the eight children studied who did not have falciparum malaria, the tl/~ of quinine was 12.70 _+ 5.5l hours, and Vd 1.43 _+ 0.48 L / k g . The differences between the half-lives and the volumes of distribution were not significant. T h e t 89 and Vd of quinine did not appear to be affected by administration of chloramphenicol (six chip
Volume 106 Number 3
Table lILBioavailability of intramuscular and nasogastric quinine
l
.
A U C +_ SD (#g/ml/hr) Hr 12
Intravenous Intramuscular Nasogastric
509
Pharrnacokinetics o f quinine
90.5 • 36.8 87.2 +_ 38.2 95.4 • 54.4
% IV
Hr 50
% IV
96 109
187.7 -+ 92.2 143.3 • 80.9 224.3 • 164.6
76 119
I
I
T ,,,
9
20
,=. ,,,
Z
15
Z
|
C2~ dren), paraldehyde (three children), or amodiaquine (three children). Multiple linear regression analysis failed to show a significant relationship between the tV2 or the clearance of quinine and age, temperature, serum bilirubin concentration, or degree of parasitemia. At 12 hours, the difference between the mean A U C after intramuscular and intravenous administration of quinine dihydrochloride was small (90.5 - 87.2 = 3.3 ~g/ ml/hr), but the 95% confidence limits for the difference were large (3.3 _+ 41.9 #g/ml/hr) (Table III). Similarly, the difference between the AUC after nasogastric and intravenous administration of quinine dihydrochloride was 4.9 +_ 57.7 ~g/ml/hr at 12 hours. Presumably by chance, the tl/z of quinine in the intramuscular group was shorter than in the intravenous group, so at 50 hours the intramuscular AUC was only 76% of the intravenous AUC. The t~A of quinine in the nasogastric group was longer than in the intravenous group, so at 50 hours the nasogastric AUC was 119% of the intravenous AUC. DISCUSSION These results indicate that quinine is rapidly and completely absorbed within 2 hours after intramuscular administration, provided the patient is not in shock. Abscess formation or severe induration was not seen, confirming the findings of an earlier study in 50 children.'~ These findings are in contrast with the conventional view that intramuscular administration results in poor absorption and causes abscessesS'9; poor absorption may have been caused by subcutaneous rather than intramuscular administration in adults, ~3and abscess formation may have been caused by nonsterile equipment or by the use of very concentrated solutions of quinine (the solution used in our study contained only 60 mg/ml quinine dihydrochloride). Quinine solution administered by nasogastric tube also appeared to be well absorbed, usually within 3 hours. However, there was a wide variation in AUC among subjects (Table III), and intravenous, intramuscular, and nasogastric administration was not studied sequentially in individual patients; therefore, the bioavailability of intramuscular and nasogastric quinine could not be determined with precision.
"-
10
LO
W El_
5
I
I
I
I NTRA-
I NTRA-
NASO-
VENOUS
MUSCULAR GASTRIC
Fig. 2. Highest recorded serum concentrations of quinine after intravenous, intramuscular, and nasogastric administration. Bars show mean values.
There was no significant difference in the tV2 or Va of quinine among children with cerebral malaria, uncomplicated malaria, or other illnesses. The tlA of quinine did not appear to be affected by age (within the pediatric population studied), temperature, serum bilirubin concentration, degree of parasitemia, or administration of chloramphenicol, paraldehyde, or amodiaquine. Studies in adults have shown a wide variation in the 0/2 and Vd of quinine. White et al. 7 found that dA ranged from 18.2 _+ 9.7 hours in cerebral malaria to 11.1 + 4.1 hours after recovery. The Vo was 1.18 +_ 0.37 L/kg in cerebral malaria and 2.74 _+ 0.47 L/kg after recovery. Berlin et al. 6 found that the tY2 of quinine was dose dependent and ranged from 8.5 +_ 3.4 hours with 100 mg quinine three times a day to 16.4 ___4.2 hours with 650 mg quinine in healthy volunteers. Hall 4 reported a tth of 19 hours in falciparum malaria, compared with 10 hours in healthy volunteers. Our results in children also showed a wide variation in the tV2 and Vd of.quinine. The tV2 of quinine in children appears to be somewhat shorter than in adults, being 11.1 _+ 4.8 hours in the 21 children studied, all of whom were acutely ill. There was no consistent change in the tV2 in six children who were restudied after 5 days of treatment, but the 0/2 for day 5 was calculated from only two
5 10
Shann, Stace, and Edstein
serum concentrations for each child, 1 hour and 12 hours after injection. The Vd of quinine in the 21 children studied Was 1.39 _+ 0.37 L / k g , similar to that in the adults with falciparum malaria studied by White et al. 7 Unlike White et al., we were unable to show a relationship between the tl/~ or Vd of quinine and the severity of the illness, but we studied only 21 patients. It is generally held that, because of the likelihood of toxicity, serum quinine levels should not exceed 10 # g / ml. ~4 However, Chongsuphajaisiddhi et al. ~5 have reported that the mean M I C of quinine for P. falciparum is now approaching 20 u g / m l in Thailand and that treatment with quinine is unsuccessful unless serum quinine concentrations are maintained above the M I C for 7 days. White et al. 7 have shown that, at levels of 10 to 20 u g / m l , serious cardiotoxicity and neurotoxicity are unlikely. Tinnitus and headache often occur in adults at this serum level, but these relatively minor side effects may have to be accepted in the management of life-threatening falciparum malaria. If a serum level of 10 # g / m l quinine is required, we suggest that children be given a loading dose of 20 m g / k g quinine dihydrochloride by intravenous infusion over 4 hours, followed by 7.5 m g / k g infused over 2 hours, every 8 hours. Once the child begins to recover, 10 m g / k g quinine sulphate could be given orally every 8 hours. This higher dose is suggested because the half-life of quinine usually falls during the recovery periodY .6'7 Because of the wide variation in quinine tl/z and Vd and the narrow therapeutic range of the drug, serum levels of quinine should be monitored if possible. In less developed countries it may be impractical to give a loading dose of quinine followed by intravenous infusions three times a day; quinine dihydrochloride 15 m g / k g could be given by deep intramuscular injection every 12 hours for four doses, followed by l0 m g / k g quinine sulphate orally three times a day. Higher doses of quinine may be required in infections with P. faleiparum that has reduced susceptibility to quinine.
The Journal of Pediatrics March 1985
REFERENCES
1. Centers for Disease Control: Malaria surveillance: Annual summary 1980. Atlanta, [982, U.S. Public Health Service. 2. Centers for Disease ControI: Prevention of malaria in travellers 1982. MMWR 31(Suppl 1):IS, 1982. 3. Hall AP: The treatment of malaria. Br Med J 1:323, 1976. 4. Hall AP, Hanchalay S, Doberstyn ER, Bumnetphund S: Quinine dosage and serum levels of falciparum malaria. Ann Report, 1975, Medical Research Laboratories, SEATO pp 188-190. 5. Trenholme GM, Williams RL, Rieckmann KH, Frischer H, Carson PE: Quinine disposition during malaria and during induced fever. Clin Pharmacol Ther 19:459, 1976. 6. Berlin CM, Stackman JM, Vesell ES: Quinine-induced alterations in drug disposition. Clin Pharmacol Ther 18:670, 1975. 7. White N J, Looareesuwan S, Warrell DA, Warrell M J, Bunnag D, Harinasuta T: Quinine pharmacokinetics and toxicity in cerebral and uncomplicated falciparum malaria. Am J Med 73:564, 1982. 8. Hall AP: The treatment of severe falciparum malaria. Trans R Soc Trop Med Hyg 71:367, 1977. 9. Wade A, editor: Martindale: The extra pharmacopeia, ed 27. London, 1977, Pharmaceutical Press, p 358. 10. Stace J, Shann FA, Waiters S, Connellan M, Edstein M: Serum levels of quinine following intramuscular administration in children. Papua New Guinea Med J 26:21, 1983. 11. Darlow B, Vrbova H, Stace J, Heywood P, Alpers M: Fansidar-resistant falciparum malaria in Papua New Guinea. Lancet 2:1243, 1980. 12. Edstein M, Stace J, Shann FA: Quantification of quinine in human serum by high-performance liquid chromatography. J Chromatogr 278:445, 1983. 13. Cockshott WP, Thompson GT, Howlett L J, Seeley ET: Intramuscular or intralipomatous injections? N Engl J Med 307:356, 1982. 14. Powell D, McNamara JV: Quinine: Side effects and plasma levels. Proc Helminth Soc Wash 39:51, 1972. 15. Chongsuphajaisiddhi T, Sabchareon A, Attanath P: Treatment of quinine-resistant falciparum malaria in Thai children. Southeast Asian J Trop Med Public Health 14:357, 1983.
Frank Shann, F.R.A.C.P, John Stace, M.B., B.S., and Michael Edstein, B.Sc. P a p u a N e w G u i n e a a n d Ingleburn, A u s t r a l i a
IN 1980-i981, 3316 cases of malaria were reported to the Centers for Disease Control--more than the total number of civilian cases reported in the previous 10 years. 1 The number of cases of chloroquine-resistant malaria treated in the United States is likely to increase: not only are more cases of malaria occurring, but it is probable that an increasing proportion will be insensitive to chloroquine as resistance spreads through the endemic areas of the world/ Quinine is the treatment of choice for severe chloroquineresistant falciparum malaria. 3 Although there have been some studies of the pharmacokinetics of quinine in adults, 47 very little Work has been done in children/ In the less developed countries, intravenous infusion of quinine is expensive, increases the risk of cerebral edema, and is unsuitable for use by primary health workers. Intramuscular administration of quinine does not have these disadvantages, but the drug is said to be poorly absorbed and to cause pain and tissue necrosis/' 9 However, intramuscular injections of quinine have been given for many years by medical workers in Papua New Guinea, and no serious problems have been observed, either with From the Departments of Pediatrics, Goroka Base Hospital, Madang Hospital, and the Army Malaria Research Unit. Submitted for publication March 14, 1984; accepted Aug. 13, 1984. Reprint requests: Frank Shann, F.R.A.C.P., Intensive Care Unit, Royal Children's Hospital, Parkville, Victoria 3052, Australia.
506
TheJournalofPEDIATRICS
routine clinical use or during a pilot study that was done preliminary to our investigation/~ We measured serum quinine levels in children after intravenous, intramuscular, and nasogastric administration of quinine dihydroehloride.
METHODS Malaria is endemic in the Madang area of Papua New Guinea, and chtoroquine-resistant Plasmodium falciparum is common." Cerebral malaria is diagnosed when the blood slide is positive for asexual forms of P. falciparum
M1C tVz Va
Minimum inhibitory concentration Half-life Volume of distribution
I I
I
and the patient is unarousable with no other demonstrable cause of unconsciousness. 7 However, in Madang all comatose children, including those with meningitis, are given quinine. Conscious children with falciparum malaria who do not improve with chloroquine therapy are also given quinine. All comatose children admitted to Madang Hospital between March and August 1982 were given quinine dihydrochloride either intravenously or intramuscularly. Allocation to intravenous or intramuscular treatment was not random; intravenous treatment was given only when the ward was not too busy. Quinine dihydrochloride was
Volume 106 Number 3
Pharmacokinetics o f quinine
507
Table I. Characteristics of children studied Quinine administration
Intravenous Intramuscular Nasogastric
Range
Maximum temperature (~C) (mean + SD)
Total serum biIirubin (~g/ml) (mean +_SD)
1 to 96 5 to 48 18 to 72
38.4 • 1.4 38.6 + 1.0 39.0 • 1.3
0.29 • 0.24 0.54 • 0.56 0.52 _+ 0.28
Age (too)
P. falciparum positive
Mean
3 of 7 6 of 8 4 of 6
33 30 41
given via nasogastric tube to all conscious children with malaria not responding to chtoroquine therapy. Verbal consent was obtained from the parent(s) of each child. The study was approved by the Papua New Guinea Medical Research Advisory Committee. The ages of the children studied ranged from 1 to 96 months (Table I). After a pilot study of quinine levels in children in Papua New Guinea, ~~it was decided to give a dose of 300 mg/m z quinine dihydrochloride (Rotexmedica 60 mg/ml, 57.1 mg/ml quinine base). In seven children, 300 mg/m 2 quinine dihydrochloride was infused dntravenously over 4 hours. Venous blood samples were taken from the opposite arm at 0, 2, 4, 6, and 12 hours, and in three children 24 hours, after the start of the infusion. Eight children were given 300 mg/m 2quinine dihydrochloride by deep intramuscular injection from a glass syringe, and venous blood samples were taken after 1, 2, 6, and 12 hours. Six of the eight children were restudied after having received 300 mg/m 2 quinine dihydrochloride intramuscularly every 12 hours for 5 days. The sites of injection were inspected daily for evidence of induration or abscess formation. In six children quinine dihydrochloride was administered by nasogastric tube; the parenteral solution was used rather than tablets. Blood samples were taken 0, 3, 6, 9, 12, and 18 hours after nasogastric administration. After collection, the blood was centrifuged and the serum stored at - 2 0 ~ C. Levels of quinine (base) were measured by high-performance liquid chromatography. Several aspects of the collection and storage of samples and the assay of quinine were studied; the details have been published elsewhere. ~2 For each child a thick and thin blood film was examined for malarial parasites. Table I shows the number of blood slides positive for P. falciparum. In one of the two children in the nasogastric quinine group, the blood film was negative for P. falciparum, but positive for P. vivax. In each child serum bilirubin was measured on admission and body temperature recorded every 4 hours. The elimination half-tile of quinine was calculated for each child individually from the terminal log-linear portion of the concentration-time curve by calculating the regres-
sion of the logarithm of the serum concentration of quinine against time by the least-squares method. To calculate the volume of distribution of quinine, the serum levels for each child were plotted On graph paper and the plot extended to 50 hours using the calculated half-life for that child. The area under the curve was determined by weighing. The volume of distribution was calculated from the formula V~ = (Dose • tl/2)/(AUC X 0.693) where the dose of quinine base was expressed in milligrams per kilogram, tlA was the half-life in hours, and AUC was the area under the serum concentration curve i n micrograms per milliliter per hour. RESULTS Serum quinine concentrations were measured in seven patients after intravenous infusion of quinine dihydrochloride, in eight patients after intramuscular injection, and in six patients after nasogastric administration (Table II and Fig. 1). In the three groups combined, the 300 mg/m 2 dose of quinine dihydrochloride averaged (mean _+ SD) 14.6 _+ 1.8 mg/kg (13.9 _+ 1.7 mg/kg base). After the end of the 4-hour intravenous infusion of quinine dihydrochloride, the logarithmic concentration of quinine declined in a linear fashion in all seven patients. The tF2 in this group was 12.47 _+ 4.01 hours, and Vd 1.51 + 0.39 L/kg. After intramuscular administration, quinine dihydrochloride was rapidly absorbed. The highest concentration was measured at 1 hour in five of the eight children studied, and at 2 hours in the other three (in one of these, no sample was taken at 1 hour) (Fig. 2). The logarithmic concentration of quinine declined in a linear fashion from 1 hour after intramuscular injection in five of the eight patients studied and from 2 hours after injection in the other three (in one of these, no sample was taken at 1 hour). The tV2 of-Nhinine in this group was 8.35 • 2.78 hours, and Vd 1.29 • L/kg. In six children, quinine dihydrochloride 300 mg/m 2 was given ]ntramuscularly every 12 hours, and serum levels of the drug were measured again on day 5. The mean serum quinine concentra-
508
Shann, Stace, and Edstein
The Journal of Pediatrics March 1985
12
8
Ir
"-Z'--..'."-..
.~
*"..
~
"* NASOGASTRIC
INTRAMUSCULAR
0
I
2.
I
I
4
6
j
8
"'...
I
1
'1
]
1
I
~
1
10
12
14
16
18
20
22
24
HOURS Fig. 1. Mean serum concentrations of quinine after intravenous, intramuscular, and nasogastric administration.
Table IL S e r u m concentrations of quinine after intravenous, intramuscular, and nasogastric administration
Serum quinine (gg/ml Intravenous infusion
t89 (hr)
Vd (hr)
Hr 0 0.0 • 0.0 (7)
Hr 2 8.5 + 3.2 (6)
Hr 4 9.7 • 3.7 (7)
Hr 6 8.2_+ 3.2 (7)
Hr 12 5.8 • 3.1 (7)
Hr 24 3.1 _+ 0.9 (3)
12.5_+4.0
1.5 • 0.4
Hr 0 0.0 --4-0.0 (6)
Hr 1 10.6 • 4.4 (7)
Hr 2 10.0 • 4.0 (8)
Hr 6 7.4 • 3.5 (8)
Hr 12 4.3 • 2.5 (8)
--
8.4 + 2.8
1.3 _+ 0.3
Hr 0 0.0 • 0.0 (6)
Hr 3 10.3 + 5.7 (6)
Hr6 8.9 • 4.8 (6)
Hr9 8.6_+ 6.6 (4)
Hr 12 6.9_+ 4.9 (6)
Hr 18 5.2 • 4.8 (6)
13.1 _+ 6.5
].4_+ 0.5
(n = 7)
Intramuscular injection (n = 8)
Nasogastric administration (n = 6)
Values represent mean _+SD; number of children in parentheses.
tion was I 1.3 .+ 4.0 # g / m l 1 hour after the injection, and 6.5 _+ 4.6 # g / m l at 12 hours. T h e t 89 was 9.8 _+ 1.9 hours. After nasogastric administration of quinine dihydrochloride, the highest recorded serum concentration occurred at 3 hours in five of the six children studied and at 6 hours in one child (Fig. 2). Linear decline in the logarithmic concentration occurred after 3 hours in four of the six children and after 9 hours in one child. T h e m e a n t 89 in this group was 13.13 .+ 6.46 hours and the Vd was 1.38 _+ 0.48 L / k g .
T h e t 89 of quinine in the four children with cerebral malaria was 8.48 _ 2.56 hours, and Vd 1.44 _ 0.01 L / k g . In the nine conscious children with falciparum malaria, the t 89 of quinine was 10.82 _+ 4.69 hours, and Vd 1.33 _+ 0.37 L / k g . In the eight children studied who did not have falciparum malaria, the tl/~ of quinine was 12.70 _+ 5.5l hours, and Vd 1.43 _+ 0.48 L / k g . The differences between the half-lives and the volumes of distribution were not significant. T h e t 89 and Vd of quinine did not appear to be affected by administration of chloramphenicol (six chip
Volume 106 Number 3
Table lILBioavailability of intramuscular and nasogastric quinine
l
.
A U C +_ SD (#g/ml/hr) Hr 12
Intravenous Intramuscular Nasogastric
509
Pharrnacokinetics o f quinine
90.5 • 36.8 87.2 +_ 38.2 95.4 • 54.4
% IV
Hr 50
% IV
96 109
187.7 -+ 92.2 143.3 • 80.9 224.3 • 164.6
76 119
I
I
T ,,,
9
20
,=. ,,,
Z
15
Z
|
C2~ dren), paraldehyde (three children), or amodiaquine (three children). Multiple linear regression analysis failed to show a significant relationship between the tV2 or the clearance of quinine and age, temperature, serum bilirubin concentration, or degree of parasitemia. At 12 hours, the difference between the mean A U C after intramuscular and intravenous administration of quinine dihydrochloride was small (90.5 - 87.2 = 3.3 ~g/ ml/hr), but the 95% confidence limits for the difference were large (3.3 _+ 41.9 #g/ml/hr) (Table III). Similarly, the difference between the AUC after nasogastric and intravenous administration of quinine dihydrochloride was 4.9 +_ 57.7 ~g/ml/hr at 12 hours. Presumably by chance, the tl/z of quinine in the intramuscular group was shorter than in the intravenous group, so at 50 hours the intramuscular AUC was only 76% of the intravenous AUC. The t~A of quinine in the nasogastric group was longer than in the intravenous group, so at 50 hours the nasogastric AUC was 119% of the intravenous AUC. DISCUSSION These results indicate that quinine is rapidly and completely absorbed within 2 hours after intramuscular administration, provided the patient is not in shock. Abscess formation or severe induration was not seen, confirming the findings of an earlier study in 50 children.'~ These findings are in contrast with the conventional view that intramuscular administration results in poor absorption and causes abscessesS'9; poor absorption may have been caused by subcutaneous rather than intramuscular administration in adults, ~3and abscess formation may have been caused by nonsterile equipment or by the use of very concentrated solutions of quinine (the solution used in our study contained only 60 mg/ml quinine dihydrochloride). Quinine solution administered by nasogastric tube also appeared to be well absorbed, usually within 3 hours. However, there was a wide variation in AUC among subjects (Table III), and intravenous, intramuscular, and nasogastric administration was not studied sequentially in individual patients; therefore, the bioavailability of intramuscular and nasogastric quinine could not be determined with precision.
"-
10
LO
W El_
5
I
I
I
I NTRA-
I NTRA-
NASO-
VENOUS
MUSCULAR GASTRIC
Fig. 2. Highest recorded serum concentrations of quinine after intravenous, intramuscular, and nasogastric administration. Bars show mean values.
There was no significant difference in the tV2 or Va of quinine among children with cerebral malaria, uncomplicated malaria, or other illnesses. The tlA of quinine did not appear to be affected by age (within the pediatric population studied), temperature, serum bilirubin concentration, degree of parasitemia, or administration of chloramphenicol, paraldehyde, or amodiaquine. Studies in adults have shown a wide variation in the 0/2 and Vd of quinine. White et al. 7 found that dA ranged from 18.2 _+ 9.7 hours in cerebral malaria to 11.1 + 4.1 hours after recovery. The Vo was 1.18 +_ 0.37 L/kg in cerebral malaria and 2.74 _+ 0.47 L/kg after recovery. Berlin et al. 6 found that the tY2 of quinine was dose dependent and ranged from 8.5 +_ 3.4 hours with 100 mg quinine three times a day to 16.4 ___4.2 hours with 650 mg quinine in healthy volunteers. Hall 4 reported a tth of 19 hours in falciparum malaria, compared with 10 hours in healthy volunteers. Our results in children also showed a wide variation in the tV2 and Vd of.quinine. The tV2 of quinine in children appears to be somewhat shorter than in adults, being 11.1 _+ 4.8 hours in the 21 children studied, all of whom were acutely ill. There was no consistent change in the tV2 in six children who were restudied after 5 days of treatment, but the 0/2 for day 5 was calculated from only two
5 10
Shann, Stace, and Edstein
serum concentrations for each child, 1 hour and 12 hours after injection. The Vd of quinine in the 21 children studied Was 1.39 _+ 0.37 L / k g , similar to that in the adults with falciparum malaria studied by White et al. 7 Unlike White et al., we were unable to show a relationship between the tl/~ or Vd of quinine and the severity of the illness, but we studied only 21 patients. It is generally held that, because of the likelihood of toxicity, serum quinine levels should not exceed 10 # g / ml. ~4 However, Chongsuphajaisiddhi et al. ~5 have reported that the mean M I C of quinine for P. falciparum is now approaching 20 u g / m l in Thailand and that treatment with quinine is unsuccessful unless serum quinine concentrations are maintained above the M I C for 7 days. White et al. 7 have shown that, at levels of 10 to 20 u g / m l , serious cardiotoxicity and neurotoxicity are unlikely. Tinnitus and headache often occur in adults at this serum level, but these relatively minor side effects may have to be accepted in the management of life-threatening falciparum malaria. If a serum level of 10 # g / m l quinine is required, we suggest that children be given a loading dose of 20 m g / k g quinine dihydrochloride by intravenous infusion over 4 hours, followed by 7.5 m g / k g infused over 2 hours, every 8 hours. Once the child begins to recover, 10 m g / k g quinine sulphate could be given orally every 8 hours. This higher dose is suggested because the half-life of quinine usually falls during the recovery periodY .6'7 Because of the wide variation in quinine tl/z and Vd and the narrow therapeutic range of the drug, serum levels of quinine should be monitored if possible. In less developed countries it may be impractical to give a loading dose of quinine followed by intravenous infusions three times a day; quinine dihydrochloride 15 m g / k g could be given by deep intramuscular injection every 12 hours for four doses, followed by l0 m g / k g quinine sulphate orally three times a day. Higher doses of quinine may be required in infections with P. faleiparum that has reduced susceptibility to quinine.
The Journal of Pediatrics March 1985
REFERENCES
1. Centers for Disease Control: Malaria surveillance: Annual summary 1980. Atlanta, [982, U.S. Public Health Service. 2. Centers for Disease ControI: Prevention of malaria in travellers 1982. MMWR 31(Suppl 1):IS, 1982. 3. Hall AP: The treatment of malaria. Br Med J 1:323, 1976. 4. Hall AP, Hanchalay S, Doberstyn ER, Bumnetphund S: Quinine dosage and serum levels of falciparum malaria. Ann Report, 1975, Medical Research Laboratories, SEATO pp 188-190. 5. Trenholme GM, Williams RL, Rieckmann KH, Frischer H, Carson PE: Quinine disposition during malaria and during induced fever. Clin Pharmacol Ther 19:459, 1976. 6. Berlin CM, Stackman JM, Vesell ES: Quinine-induced alterations in drug disposition. Clin Pharmacol Ther 18:670, 1975. 7. White N J, Looareesuwan S, Warrell DA, Warrell M J, Bunnag D, Harinasuta T: Quinine pharmacokinetics and toxicity in cerebral and uncomplicated falciparum malaria. Am J Med 73:564, 1982. 8. Hall AP: The treatment of severe falciparum malaria. Trans R Soc Trop Med Hyg 71:367, 1977. 9. Wade A, editor: Martindale: The extra pharmacopeia, ed 27. London, 1977, Pharmaceutical Press, p 358. 10. Stace J, Shann FA, Waiters S, Connellan M, Edstein M: Serum levels of quinine following intramuscular administration in children. Papua New Guinea Med J 26:21, 1983. 11. Darlow B, Vrbova H, Stace J, Heywood P, Alpers M: Fansidar-resistant falciparum malaria in Papua New Guinea. Lancet 2:1243, 1980. 12. Edstein M, Stace J, Shann FA: Quantification of quinine in human serum by high-performance liquid chromatography. J Chromatogr 278:445, 1983. 13. Cockshott WP, Thompson GT, Howlett L J, Seeley ET: Intramuscular or intralipomatous injections? N Engl J Med 307:356, 1982. 14. Powell D, McNamara JV: Quinine: Side effects and plasma levels. Proc Helminth Soc Wash 39:51, 1972. 15. Chongsuphajaisiddhi T, Sabchareon A, Attanath P: Treatment of quinine-resistant falciparum malaria in Thai children. Southeast Asian J Trop Med Public Health 14:357, 1983.