Development of an Indinavir Oral Liquid for Children
Development of an Indinavir Oral Liquid for Children
An indinavir oral liquid was developed and studied.
Several oral liquids containing indinavir were prepared and taste tested in eight healthy volunteers. Physical and chemical stability over two weeks were examined, and a randomized, two-way-crossover, single- dose bioequivalence trial was performed in 12 healthy male volunteers. Indinavir 800 mg was given as two 400-mg indinavir capsules (Crixivan) on day 1 and as 80 mL of the indinavir liquid on day 2, or vice versa. A standard breakfast and lunch were given at fixed times, and blood and urine samples were collected at various intervals up to eight hours. The log-transformed area under the concentration-versus- time curve from zero to eight hours (AUC0-8) and maximum plasma concentration (Cmax ) for the liquid versus the capsules were compared by using a 90% confidence interval (CI) test (limits, 80-125%), and the time to Cmax (tmax) was compared by using the nonparametric sign test.
The liquid selected had an acceptable taste, contained indinavir 10 mg/mL, and was chemically stable for two weeks at 4 °C. The 90% CI for the AUC ratio (liquid versus capsules) was 92-99% (mean, 95%); for the Cmax ratio it was 95-106% (mean, 100%). There was no significant difference in tmax between the liquid and capsules.
An oral liquid formulation of indinavir was developed that had an acceptable taste, was chemically stable, and was bioequivalent to the commercially available capsule.
Since the introduction of potent combination antiretroviral therapy involving HIV protease inhibitors, triple-drug therapy consisting of two nucleoside analogue reverse-transcriptase inhibitors and one protease inhibitor has been used most often. Combinations with two protease inhibitors are also used. Non-nucleo-side- analogue reverse-transcriptase inhibitors can be added to these regimens or can be used in protease inhibitor- sparing regimens. Reverse-transcriptase inhibitors exert their effect early in the viral replication cycle, and protease inhibitors prevent the virus from maturing.
Combination antiretroviral therapy has been used in adults for about three years. In children, triple-drug therapy was introduced more recently. Because of the availability of pediatric formulations of the protease inhibitors ritonavir (liquid) and nelfinavir (powder) in the United States, these were the protease inhibitors that were studied first in combination antiretroviral regimens for children. Indinavir and saquinavir have been studied less in children because of the absence of specific pediatric formulations, except for indinavir 200-mg capsules, which are used in older children who are able to swallow capsules.
In the Netherlands, a study evaluating triple-drug therapy in children was begun in the spring of 1997. Indinavir was chosen because the Netherlands had no pediatric formulations registered at that time, while adult data existed for indinavir. Children could be included independent of their age, so there was a need for Development of an indinavir oral liquid for children flexible dosing. The dosage was based on the metabolic weight (MW = body weight 0.75 ) of the child; plasma samples were drawn after four weeks to determine whether dosage adjustment was necessary. The goal was to provide pharmacokinetic data comparable to the adult data. It appeared that most children needed an adjustment in the initial dosage of 100 mg per kilogram of MW. This resulted in an average dosage of 150 mg per kilogram of MW per day given in three or four doses.
In addition to the commercially available capsules of 200 and 400 mg, this study used 150-mg capsules prepared by the hospital pharmacy for administration to young children (six months of age or older). The capsules had to be opened and mixed with water for younger children because they had difficulty swallowing them. Indinavir has a very bitter taste, and the requirement that it be taken on an empty stomach makes administration with a palatable vehicle, such as custard, porridge, or chocolate milk, impossible. The inaccuracy of administration and the bad taste resulting from mixing indinavir with water raised the question whether an indinavir oral liquid could be developed.
This article describes the development and study of an indinavir oral liquid for children that is bioequivalent to the commercially available capsule.
An indinavir oral liquid was developed and studied.
Several oral liquids containing indinavir were prepared and taste tested in eight healthy volunteers. Physical and chemical stability over two weeks were examined, and a randomized, two-way-crossover, single- dose bioequivalence trial was performed in 12 healthy male volunteers. Indinavir 800 mg was given as two 400-mg indinavir capsules (Crixivan) on day 1 and as 80 mL of the indinavir liquid on day 2, or vice versa. A standard breakfast and lunch were given at fixed times, and blood and urine samples were collected at various intervals up to eight hours. The log-transformed area under the concentration-versus- time curve from zero to eight hours (AUC0-8) and maximum plasma concentration (Cmax ) for the liquid versus the capsules were compared by using a 90% confidence interval (CI) test (limits, 80-125%), and the time to Cmax (tmax) was compared by using the nonparametric sign test.
The liquid selected had an acceptable taste, contained indinavir 10 mg/mL, and was chemically stable for two weeks at 4 °C. The 90% CI for the AUC ratio (liquid versus capsules) was 92-99% (mean, 95%); for the Cmax ratio it was 95-106% (mean, 100%). There was no significant difference in tmax between the liquid and capsules.
An oral liquid formulation of indinavir was developed that had an acceptable taste, was chemically stable, and was bioequivalent to the commercially available capsule.
Since the introduction of potent combination antiretroviral therapy involving HIV protease inhibitors, triple-drug therapy consisting of two nucleoside analogue reverse-transcriptase inhibitors and one protease inhibitor has been used most often. Combinations with two protease inhibitors are also used. Non-nucleo-side- analogue reverse-transcriptase inhibitors can be added to these regimens or can be used in protease inhibitor- sparing regimens. Reverse-transcriptase inhibitors exert their effect early in the viral replication cycle, and protease inhibitors prevent the virus from maturing.
Combination antiretroviral therapy has been used in adults for about three years. In children, triple-drug therapy was introduced more recently. Because of the availability of pediatric formulations of the protease inhibitors ritonavir (liquid) and nelfinavir (powder) in the United States, these were the protease inhibitors that were studied first in combination antiretroviral regimens for children. Indinavir and saquinavir have been studied less in children because of the absence of specific pediatric formulations, except for indinavir 200-mg capsules, which are used in older children who are able to swallow capsules.
In the Netherlands, a study evaluating triple-drug therapy in children was begun in the spring of 1997. Indinavir was chosen because the Netherlands had no pediatric formulations registered at that time, while adult data existed for indinavir. Children could be included independent of their age, so there was a need for Development of an indinavir oral liquid for children flexible dosing. The dosage was based on the metabolic weight (MW = body weight 0.75 ) of the child; plasma samples were drawn after four weeks to determine whether dosage adjustment was necessary. The goal was to provide pharmacokinetic data comparable to the adult data. It appeared that most children needed an adjustment in the initial dosage of 100 mg per kilogram of MW. This resulted in an average dosage of 150 mg per kilogram of MW per day given in three or four doses.
In addition to the commercially available capsules of 200 and 400 mg, this study used 150-mg capsules prepared by the hospital pharmacy for administration to young children (six months of age or older). The capsules had to be opened and mixed with water for younger children because they had difficulty swallowing them. Indinavir has a very bitter taste, and the requirement that it be taken on an empty stomach makes administration with a palatable vehicle, such as custard, porridge, or chocolate milk, impossible. The inaccuracy of administration and the bad taste resulting from mixing indinavir with water raised the question whether an indinavir oral liquid could be developed.
This article describes the development and study of an indinavir oral liquid for children that is bioequivalent to the commercially available capsule.
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