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Rashmi H. Barbhaiya - One of the best experts on this subject based on the ideXlab platform.
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A pharmacokinetic interaction study of Didanosine coadministered with trimethoprim and/or sulphamethoxazole in HIV seropositive asymptomatic male patients
British Journal of Clinical Pharmacology, 1996Co-Authors: Nuggehally R. Srinivas, Catherine A. Knupp, Byron E. Batteiger, Robert A. Smith, Rashmi H. BarbhaiyaAbstract:1. The pharmacokinetics of Didanosine, trimethoprim, and sulphamethoxazole were evaluated in ten HIV seropositive asymptomatic patients as single agents and upon coadministration of single doses. 2. Using a randomized, balanced incomplete block crossover study with at least a 1-week washout period between successive treatments, each patient under fasting conditions received four of the following five treatments: 200 mg Didanosine as a single agent; 200 mg trimethoprim + 1000 mg sulphamethoxazole; 200 mg trimethoprim + 200 mg Didanosine; 1000 mg sulphamethoxazole + 200 mg of Didanosine and; 200 mg trimethoprim + 1000 mg sulphamethoxazole + 200 mg Didanosine. 3. Serial blood and urine samples were collected following the administration of each treatment. Plasma and urine samples were analyzed using high-pressure liquid chromatography (h.p.l.c.)/ultraviolet assays specific for unchanged Didanosine, trimethoprim and/or sulphamethoxazole. 4. Percent urinary recovery (%UR) and renal clearance (CLR) emerged as consistently affected parameters, being decreased in the case of Didanosine (35%, P = 0.016) and trimethoprim (32%, P = 0.019) and increased in the case of sulphamethoxazole (39%, P = 0.079), when all three agents were coadministered. The magnitude of the changes in Didanosine CLR and %UR values was no greater when both trimethoprim and sulphamethoxazole were coadministered vs when each single agent was given with Didanosine, suggesting that any effect was not additive. 5. Other key parameters such as Cmax, AUC, and t1/2 for Didanosine (1309.9 ng ml-1, 1796.9 ng ml-1 h, and 1.61 h, respectively), trimethoprim (1.96 micrograms ml-1, 22.86 micrograms ml-1 h, and 9.03 h, respectively) or sulphamethoxazole (58.62 micrograms ml-1, 799.7 micrograms ml-1 h and 9.84 h, respectively) were not affected when Didanosine was coadministered with either trimethoprim (Didanosine: 1751.9 ng ml-1, 2158.0 ng ml-1 h, and 1.28 h; trimethoprim: 1.81 micrograms ml-1, 28.89 micrograms ml-1 h, and 11.4 h), sulphamethoxazole (Didanosine: 1279.3 ng ml-1, 1793.2 ng ml-1 h, and 1.61 h; sulphamethoxazole: 53.57 micrograms ml-1, 732.1 micrograms ml-1 h, and 8.95 h), or the combination of trimethoprim and sulphamethoxazole (Didanosine: 1283.7 ng ml-1, 1941.8 ng ml-1 h, and 1.38 h; trimethoprim: 1.59 micrograms ml-1, 26.68 micrograms ml-1 h, and 11.3 h; sulphamethoxazole: 59.48 micrograms ml-1, 760.9 micrograms ml-1 h, and 9.47 h). 6. Because the observed differences in CLR and %UR are small and not considered to be clinically relevant, it is not necessary to alter the dosing regimens of Didanosine, trimethoprim or sulphamethoxazole when administered in combination to HIV seropositive patients.
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Effect of metoclopramide and loperamide on the pharmacokinetics of Didanosine in HIV seropositive asymptomatic male and female patients.
European Journal of Clinical Pharmacology, 1993Co-Authors: Catherine A. Knupp, Rochelle L. Milbrath, Rashmi H. BarbhaiyaAbstract:The pharmacokinetics of orally-administered Didanosine were evaluated in 6 male and 6 female HIV seropositive patients to determine the effect of pretreatment with metoclopramide, an inducer of gastrointestinal motility, and loperamide, which retards motility. Using a randomized, balanced, crossover design, each patient received the following three treatments under fasting conditions: Didanosine as a single agent, Didanosine 5 min after a single 10 mg intravenous dose of metoclopramide, and Didanosine 1 h after the final of 4 doses, 4 mg each, of loperamide. Serial blood and urine samples were collected for up to 12 h after each dose. Plasma and urine aliquots were analysed for intact Didanosine using HPLC with UV detection. Pharmacokinetic parameter values were calculated using noncompartmental methods.
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Biopharmaceutics of Didanosine in Humans and in a Model for Acid-Labile Drugs, the Pentagastrin-Pretreated Dog
Pharmaceutical Research, 1993Co-Authors: Catherine A. Knupp, Wen Chyi Shyu, Elizabeth A. Morgenthien, Rashmi H. BarbhaiyaAbstract:Didanosine is a purine nucleoside analogue approved for the treatment of human immunodeficiency virus infection. It is extremely unstable at pH values less than 3 and requires protection against gastric acid-induced hydrolysis. Beagle dogs pretreated with pentagastrin, an analogue of gastrin that reproducibly stimulates gastric acid secretion, have been used to screen different Didanosine formulations. The absolute bioavailability of Didanosine from a saline solution decreased from approximately 43% in untreated dogs to 8% after pretreatment with pentagastrin. Administration of buffered solution of Didanosine to untreated and pretreated dogs yielded bio-availability estimates of 37 and 30%, respectively. In humans, the bioavailability from a similar buffered solution was approximately 40%. Pentagastrin-pretreated dogs were used to evaluate four new products relative to a citrate-phosphate buffer sachet, the formulation selected for large-scale clinical trials in humans. Two of these new formulations, a chewable tablet and an antacid suspension, were more bioavailable then the reference sachet. This also proved to be true in man, necessitating an adjustment in the dose of Didanosine when administered as the chewable tablet. Dogs pretreated with pentagastrin accurately predicted the improved bioavailability of new Didanosine formulations prior to clinical use. This animal model may be helpful in evaluating the biopharmaceutics of other acid-labile drugs.
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Absorption, disposition, and metabolism of [14C]Didanosine in the beagle dog.
Drug Metabolism and Disposition, 1993Co-Authors: Sanjeev Kaul, Wen Chyi Shyu, U. A. Shukla, K.a. Dandekar, Rashmi H. BarbhaiyaAbstract:The absorption, disposition, and metabolism of Didanosine were investigated in three adult male beagle dogs that received a single iv and po solution dose of 200 mg (ca. 20 mg/kg) of [14C]Didanosine. The dog model was "humanized" by predosing with pentagastrin (6 micrograms/kg). The po dose was in buffer, as administered in man. The iv and po sessions were separated by 1 week. Plasma, urine, and feces were collected and assayed for total radioactivity; plasma and urine samples were also analyzed for intact Didanosine using validated HPLC/UV assays. Metabolic profiles of [14C]Didanosine were obtained in plasma and urine. After iv dose, 87% and 0.5% of the administered radioactivity were recovered in urine and feces within 6 days, respectively; the corresponding recoveries were 84% and 2.1% after po dose. Oral absorption of Didanosine was rapid and complete; but due to first pass metabolism, the absolute bioavailability of Didanosine was 44%. Mean renal clearance of Didanosine (110 ml/min) accounted for about 43% of the total body clearance. The mean steady state volume of distribution of Didanosine was 9.6 liters. The mean terminal half-life of Didanosine was 0.8 hr after iv or po administration. Five putative metabolites, M1 (allantoin), M2, M3 (uric acid), M4 (hypoxanthine), and M5 (xanthine) of Didanosine were observed in plasma and/or urine. The sum of the five metabolites plus unchanged drug accounted for virtually all of the radioactivity in plasma and urine. Allantoin represented the major metabolite in both plasma and urine. The extent of metabolism and the proportion of dose excreted as unchanged Didanosine were markedly route dependent.(ABSTRACT TRUNCATED AT 250 WORDS)
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Pharmacokinetic-interaction study of Didanosine and ranitidine in patients seropositive for human immunodeficiency virus.
Antimicrobial Agents and Chemotherapy, 1992Co-Authors: Catherine A. Knupp, F M Graziano, R M Dixon, Rashmi H. BarbhaiyaAbstract:The potential pharmacokinetic interactions between Didanosine, an acid-labile antiretroviral agent, and ranitidine, an H2-receptor antagonist, were evaluated by a crossover study of 12 male patients seropositive for the human immunodeficiency virus. Single oral doses of 375 mg of Didanosine, formulated as a citrate-phosphate-buffered sachet, or of 150 mg of ranitidine were administered alone or in combination (ranitidine was given 2 h prior to Didanosine). Serial blood samples and total urinary output were collected after each treatment and analyzed for Didanosine and/or ranitidine by validated high-performance liquid chromatography-UV assay methods. Pharmacokinetic parameters were calculated by noncompartmental methods. There were significant increases in mean area under the curve from time zero to infinity and mean urinary recovery for Didanosine given in combination with ranitidine compared with those for Didanosine alone. There were no significant differences between Didanosine coadministered with ranitidine and Didanosine alone in the respective mean peak concentrations in plasma, times to peak, elimination half-lives, or renal clearances. The mean area under the curve for ranitidine given with Didanosine was significantly less than that for ranitidine given alone. There were no significant differences between the mean peak concentrations in plasma, times to peak, elimination half-lives, renal clearances, or urinary recovery values for ranitidine coadministered with Didanosine and values for ranitidine given alone. These data demonstrate that administration of Didanosine 2 h after ranitidine will result in a minor increase in the bioavailability of Didanosine. A modification in the dose of Didanosine or ranitidine is not necessary if the dose of ranitidine precedes that of Didanosine by 2 h.
Carla Pettinelli - One of the best experts on this subject based on the ideXlab platform.
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zidovudine alone or in combination with Didanosine or zalcitabine in hiv infected patients with the acquired immunodeficiency syndrome or fewer than 200 cd4 cells per cubic millimeter
The New England Journal of Medicine, 1996Co-Authors: Louis D Saravolatz, Carla Pettinelli, Dean L Winslow, Gary Collins, James S Hodges, Daniel S Stein, Norman Markowitz, Randall R Reves, Mark O Loveless, Lawrence R CraneAbstract:Background We compared two combinations of nucleosides with zidovudine alone in patients with advanced human immunodeficiency virus (HIV) infection. Methods A total of 1102 patients with the acquired immunodeficiency syndrome or fewer than 200 CD4 cells per cubic millimeter were randomly assigned to receive zidovudine alone or zidovudine combined with either Didanosine or zalcitabine. Disease progression, survival, toxic effects, and the CD4 cell response were assessed. Results After a median follow-up of 35 months, disease progression or death occurred in 62 percent of the 363 patients assigned to zidovudine plus Didanosine, 63 percent of the 367 assigned to zidovudine plus zalcitabine, and 66 percent of the 372 assigned to zidovudine alone (P = 0.24). As compared with zidovudine therapy, treatment with zidovudine plus Didanosine was associated with a relative risk of disease progression or death of 0.86 (95 percent confidence interval, 0.71 to 1.03), and treatment with zidovudine plus zalcitabine was as...
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zidovudine compared with Didanosine in patients with advanced hiv type 1 infection and little or no previous experience with zidovudine
JAMA Internal Medicine, 1995Co-Authors: Raphael Dolin, Margaret A. Fischl, David A Amato, Carla Pettinelli, Mohan Beltangady, Songheng Liou, Michael J Brown, Anne Cross, Martin S Hirsch, David W HardyAbstract:Background: We conducted a trial to compare treatment with zidovudine or Didanosine in patients with advanced human immunodeficiency virus type 1 (HIV-1) infection who had received little or no previous therapy with zidovudine. Methods: Six hundred seventeen patients with acquired immunodeficiency syndrome (AIDS), advanced AIDS-related complex (CD4 cell count, ≤0.30× 10 9 /L [300/μL]), or asymptomatic HIV (CD4 cell count, ≤0.20× 10 9 /L) received zidovudine, 500 mg/d of Didanosine, or 750 mg/d of Didanosine in a randomized, double-blind allocation, with cross-over to alternative medication after development of an end point or serious toxic effect. To be eligible, patients must have received either no or up to 16 weeks of zidovudine therapy before entry into the study. Primary end points were development of a new AIDS-defining event or death. Secondary clinical end points were new or recurrent AIDS-defining events, or death, and survival. Results: In the study as a whole, there were no differences in the relative risks (RRs) of the development of end points between treatment groups. However, there was a strong interaction between the relative efficacies of zidovudine and Didanosine and previous experience with zidovudine. Among 380 patients with no previous zidovudine therapy, zidovudine was more effective than 750 mg/d of Didanosine (RR, 1.43; 90% confidence interval [CI], 1.02 to 2.00), with a similar trend for zidovudine compared with 500 mg/d of Didanosine (RR, 1.21; 90% CI, 0.86 to 1.71). However, among 118 patients with more than 8 weeks but no more than 16 weeks of previous zidovudine therapy, 500 mg/d of Didanosine was more effective than zidovudine (RR, 0.48; 90% CI, 0.27 to 0.86); there was a similar trend for increased effectiveness of 750 mg/d of Didanosine compared with zidovudine (RR, 0.61; 90% CI, 0.36 to 1.03). Among 119 patients who had some but no more than 8 weeks of previous zidovudine therapy, there were no significant differences among the treatment arms. Similar findings were noted in the analysis of the two secondary clinical end points. No significant differences were found in efficacy between the groups receiving 500 and 750 mg/d of Didanosine. The major toxic effect associated with zidovudine was hematopoietic (granulocytopenia) and that associated with Didanosine was pancreatitis (dosage, 750 mg/d). Conclusions: In patients with advanced HIV disease, zidovudine appears to be more effective than Didanosine as initial therapy; however, some patients with advanced HIV disease may benefit from a change to Didanosine therapy after as little as 8 to 16 weeks of therapy with zidovudine. (Arch Intern Med. 1995;155:961-974)
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a controlled trial comparing continued zidovudine with Didanosine in human immunodeficiency virus infection
The New England Journal of Medicine, 1992Co-Authors: James O Kahn, Carla Pettinelli, Songheng Liou, Anne Cross, Stephen W Lagakos, Douglas D Richman, Michael S Brown, Paul A Volberding, Clyde S Crumpacker, Gildon N BeallAbstract:Abstract Background. Although zidovudine is effective in patients with human immunodeficiency virus (HIV) infection, its efficacy may decline with prolonged use. Didanosine is another inhibitor of HIV reverse transcriptase. We evaluated the effectiveness of changing anti-HIV treatment from zidovudine to Didanosine. Methods. This multicenter, double-blind study involved 913 patients who had tolerated zidovudine for at least 16 weeks. The patients had the acquired immunodeficiency syndrome (AIDS), AIDS-related complex with ≤300 CD4 cells per cubic millimeter, or asymptomatic HIV infection with ≤200 CD4 cells per cubic millimeter. They were randomly assigned to receive 600 mg per day of zidovudine, 750 mg per day of Didanosine, or 500 mg per day of Didanosine. Results. There were significantly fewer new AIDS-defining events and deaths among the 298 subjects assigned to 500 mg per day of Didanosine than among the subjects who continued to receive zidovudine (relative risk, 1.39; 95 percent confidence interval...
Catherine A. Knupp - One of the best experts on this subject based on the ideXlab platform.
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Effect of food and pharmacokinetic variability on Didanosine systemic exposure in HIV-infected children
AIDS Research and Human Retroviruses, 2000Co-Authors: Robert C. Stevens, Catherine A. Knupp, John H Rodman, Florence H. Yong, Vincent J. Carey, Lisa M. FrenkelAbstract:The effect of food on Didanosine bioavailability and interpatient pharmacokinetic variability was examined in children infected with human immunodeficiency virus type 1 (HIV-1). Didanosine pharmacokinetics were determined during fasting and fed conditions in HIV-infected children enrolled in the Pediatric AIDS Clinical Trials Group Protocol 144 randomized to receive Didanosine at 50 mg/m2 or 150 mg/m2 orally every 12 hr. Pharmacokinetic parameters from patients in the low (n = 39) and high (n = 38) dosing groups were not significantly different, but intersubject variability was substantial. The fraction absorbed was higher while fasting than with food (0.27 +/- 0.13 versus 0.19 +/- 0.09, p < 0.0001); the zero order absorption rate was faster (0.48 +/- 0.31 versus 0.76 +/- 0.72 hr, p = 0.003); and the plasma half-life was shorter (0.93 +/- 0.43 versus 1.39 +/ 0.65 hr, p < 0.0001). The lower fraction absorbed with food was offset by the absorption rate becoming rate limiting for elimination, resulting in si...
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A pharmacokinetic interaction study of Didanosine coadministered with trimethoprim and/or sulphamethoxazole in HIV seropositive asymptomatic male patients
British Journal of Clinical Pharmacology, 1996Co-Authors: Nuggehally R. Srinivas, Catherine A. Knupp, Byron E. Batteiger, Robert A. Smith, Rashmi H. BarbhaiyaAbstract:1. The pharmacokinetics of Didanosine, trimethoprim, and sulphamethoxazole were evaluated in ten HIV seropositive asymptomatic patients as single agents and upon coadministration of single doses. 2. Using a randomized, balanced incomplete block crossover study with at least a 1-week washout period between successive treatments, each patient under fasting conditions received four of the following five treatments: 200 mg Didanosine as a single agent; 200 mg trimethoprim + 1000 mg sulphamethoxazole; 200 mg trimethoprim + 200 mg Didanosine; 1000 mg sulphamethoxazole + 200 mg of Didanosine and; 200 mg trimethoprim + 1000 mg sulphamethoxazole + 200 mg Didanosine. 3. Serial blood and urine samples were collected following the administration of each treatment. Plasma and urine samples were analyzed using high-pressure liquid chromatography (h.p.l.c.)/ultraviolet assays specific for unchanged Didanosine, trimethoprim and/or sulphamethoxazole. 4. Percent urinary recovery (%UR) and renal clearance (CLR) emerged as consistently affected parameters, being decreased in the case of Didanosine (35%, P = 0.016) and trimethoprim (32%, P = 0.019) and increased in the case of sulphamethoxazole (39%, P = 0.079), when all three agents were coadministered. The magnitude of the changes in Didanosine CLR and %UR values was no greater when both trimethoprim and sulphamethoxazole were coadministered vs when each single agent was given with Didanosine, suggesting that any effect was not additive. 5. Other key parameters such as Cmax, AUC, and t1/2 for Didanosine (1309.9 ng ml-1, 1796.9 ng ml-1 h, and 1.61 h, respectively), trimethoprim (1.96 micrograms ml-1, 22.86 micrograms ml-1 h, and 9.03 h, respectively) or sulphamethoxazole (58.62 micrograms ml-1, 799.7 micrograms ml-1 h and 9.84 h, respectively) were not affected when Didanosine was coadministered with either trimethoprim (Didanosine: 1751.9 ng ml-1, 2158.0 ng ml-1 h, and 1.28 h; trimethoprim: 1.81 micrograms ml-1, 28.89 micrograms ml-1 h, and 11.4 h), sulphamethoxazole (Didanosine: 1279.3 ng ml-1, 1793.2 ng ml-1 h, and 1.61 h; sulphamethoxazole: 53.57 micrograms ml-1, 732.1 micrograms ml-1 h, and 8.95 h), or the combination of trimethoprim and sulphamethoxazole (Didanosine: 1283.7 ng ml-1, 1941.8 ng ml-1 h, and 1.38 h; trimethoprim: 1.59 micrograms ml-1, 26.68 micrograms ml-1 h, and 11.3 h; sulphamethoxazole: 59.48 micrograms ml-1, 760.9 micrograms ml-1 h, and 9.47 h). 6. Because the observed differences in CLR and %UR are small and not considered to be clinically relevant, it is not necessary to alter the dosing regimens of Didanosine, trimethoprim or sulphamethoxazole when administered in combination to HIV seropositive patients.
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Effect of temperature on the high‐performance liquid chromatographic separation of the anti‐HIV agents, Didanosine and stavudine
Biomedical Chromatography, 1996Co-Authors: Frank A. Stancato, Nuggehally R. Srinivas, Catherine A. KnuppAbstract:This paper examines the effect of temperature on the chromatographic separation characteristics of anti-HIV agents, Didanosine and stavudine. As a result of lowering the column temperature, an improved resolution between Didanosine and stavudine peaks is observed. Thus, lower temperatures may permit the simultaneous monitoring of Didanosine and stavudine levels.
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Effect of metoclopramide and loperamide on the pharmacokinetics of Didanosine in HIV seropositive asymptomatic male and female patients.
European Journal of Clinical Pharmacology, 1993Co-Authors: Catherine A. Knupp, Rochelle L. Milbrath, Rashmi H. BarbhaiyaAbstract:The pharmacokinetics of orally-administered Didanosine were evaluated in 6 male and 6 female HIV seropositive patients to determine the effect of pretreatment with metoclopramide, an inducer of gastrointestinal motility, and loperamide, which retards motility. Using a randomized, balanced, crossover design, each patient received the following three treatments under fasting conditions: Didanosine as a single agent, Didanosine 5 min after a single 10 mg intravenous dose of metoclopramide, and Didanosine 1 h after the final of 4 doses, 4 mg each, of loperamide. Serial blood and urine samples were collected for up to 12 h after each dose. Plasma and urine aliquots were analysed for intact Didanosine using HPLC with UV detection. Pharmacokinetic parameter values were calculated using noncompartmental methods.
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Biopharmaceutics of Didanosine in Humans and in a Model for Acid-Labile Drugs, the Pentagastrin-Pretreated Dog
Pharmaceutical Research, 1993Co-Authors: Catherine A. Knupp, Wen Chyi Shyu, Elizabeth A. Morgenthien, Rashmi H. BarbhaiyaAbstract:Didanosine is a purine nucleoside analogue approved for the treatment of human immunodeficiency virus infection. It is extremely unstable at pH values less than 3 and requires protection against gastric acid-induced hydrolysis. Beagle dogs pretreated with pentagastrin, an analogue of gastrin that reproducibly stimulates gastric acid secretion, have been used to screen different Didanosine formulations. The absolute bioavailability of Didanosine from a saline solution decreased from approximately 43% in untreated dogs to 8% after pretreatment with pentagastrin. Administration of buffered solution of Didanosine to untreated and pretreated dogs yielded bio-availability estimates of 37 and 30%, respectively. In humans, the bioavailability from a similar buffered solution was approximately 40%. Pentagastrin-pretreated dogs were used to evaluate four new products relative to a citrate-phosphate buffer sachet, the formulation selected for large-scale clinical trials in humans. Two of these new formulations, a chewable tablet and an antacid suspension, were more bioavailable then the reference sachet. This also proved to be true in man, necessitating an adjustment in the dose of Didanosine when administered as the chewable tablet. Dogs pretreated with pentagastrin accurately predicted the improved bioavailability of new Didanosine formulations prior to clinical use. This animal model may be helpful in evaluating the biopharmaceutics of other acid-labile drugs.
L Dunkle - One of the best experts on this subject based on the ideXlab platform.
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Didanosine compared with continued zidovudine therapy for hiv infected patients with 200 to 500 cd4 cells mm3 a double blind randomized controlled trial
Annals of Internal Medicine, 1995Co-Authors: Julio S G Montaner, Martin T Schechter, Anita Rachlis, John Gill, R Beaulieu, Chris Tsoukas, Janet Raboud, Bill Cameron, Horacio Salomon, L DunkleAbstract:. Objective : To compare the safety and efficacy of Didanosine with that of continued zidovudine therapy in persons with human immunodeficiency virus (HIV) infection who had received zidovudine for at least 6 months and had CD4 cell counts of 200 to 500 CD4 cells/mm 3 . . Design : Double-blind, randomized controlled trial. . Setting : 10 Canadian university-affiliated specialty clinics. . Patients : 246 patients were assigned to receive standard doses of either zidovudine or Didanosine. . Outcome Measures : The primary clinical end point was the occurrence of a new, previously undiagnosed acquired immunodeficiency syndrome (AIDS)-defining illness or death. . Results : 245 of 246 patients were eligible (118 receiving Didanosine and 127 receiving zidovudine). Sixty-six percent were asymptomatic, 30% had AIDS-related complex, and 4% had AIDS. The median baseline CD4 count was 320 cells/mm 3 . The median previous duration of zidovudine therapy was 471 days. Nine new AIDS-defining illnesses developed during the study ; all but one were in the zidovudine group (relative risk, 7.9 [95% CI, 1.0 to 63.3 ; P = 0.02]). A change to Didanosine led to a statistically significant increase in CD4 counts by week 2 that persisted until the end of the study at week 48 (P < 0.01). Viral sensitivity studies (done in 102 patients) showed that 28% of the zidovudine group and 21% of the Didanosine group had high-level in vitro resistance to zidovudine (50% inhibitory concentration greater than 0.8 μM) at baseline (P = 0.49). Only one patient in the Didanosine group developed high-level resistance to zidovudine during the study. In the zidovudine group, the cumulative probability of developing high-level resistance to zidovudine was 59% at 1 year (P = 0.01). Abdominal pain, leukopenia, and neutropenia were more frequent in the zidovudine group, and hyperuricemia was more frequent in the Didanosine group (P < 0.05). . Conclusion : In clinically stable patients with 200 to 500 CD4 cells/mm 3 who had tolerated zidovudine for at least 6 months, a change to Didanosine led to a decrease in the rate of disease progression, a sustained increase in CD4 counts, and a decrease in the chances of developing high-level resistance to zidovudine. Both drugs were generally well tolerated.
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Food-induced reduction in bioavailability of Didanosine.
Clinical Pharmacology & Therapeutics, 1991Co-Authors: Wen Chyi Shyu, Catherine A. Knupp, K A Pittman, L Dunkle, Rashmi H. BarbhaiyaAbstract:The effect of food on the pharmacokinetics of Didanosine was evaluated in an open two-way crossover study in eight male subjects who tested seropositive for the human immunodeficiency virus. Each subject received a single 375 mg oral dose of Didanosine in a chewable tablet form with or without food. Serial blood samples and the total urinary output during 12 hours were collected and assayed for intact Didanosine by validated HPLC methods. The mean (SD) values for the peak concentration (Cmax) of Didanosine in plasma were 2789 (1032) ng/ml and 1291 (536) ng/ml and for the area under the plasma concentration-time curves (AUC0-∞) were 3902 (1316) and 2083 (922) hr · ng/ml, and the urinary excretion (%UR) accounted for 21% and 11% of dose as intact Didanosine when Didanosine was given under fasting conditions and with food, respectively. The values of Cmax, AUC0-∞, and %UR were significantly lower for subjects who received Didanosine with food compared with those observed for the fasted subjects. The time to reach Cmax, mean residence time, elimination half-life, and renal clearance remained essentially the same between the two treatments. The results from this study indicated that the rates of absorption and elimination were not affected by the presence of food; however, the extent of absorption, as indicated by AUC0-∞ and %UR, was reduced significantly in the presence of food. It is recommended that Didanosine be administered under fasting conditions. Clinical Pharmacology and Therapeutics (1991) 50, 503–507; doi:10.1038/clpt.1991.175
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Food-induced reduction in bioavailability of Didanosine.
Clinical pharmacology and therapeutics, 1991Co-Authors: W C Shyu, Catherine A. Knupp, K A Pittman, L Dunkle, Rashmi H. BarbhaiyaAbstract:The effect of food on the pharmacokinetics of Didanosine was evaluated in an open two-way crossover study in eight male subjects who tested seropositive for the human immunodeficiency virus. Each subject received a single 375 mg oral dose of Didanosine in a chewable tablet form with or without food. Serial blood samples and the total urinary output during 12 hours were collected and assayed for intact Didanosine by validated HPLC methods. The mean (SD) values for the peak concentration (Cmax) of Didanosine in plasma were 2789 (1032) ng/ml and 1291 (536) ng/ml and for the area under the plasma concentration-time curves (AUC0-infinity) were 3902 (1316) and 2083 (922) hr.ng/ml, and the urinary excretion (%UR) accounted for 21% and 11% of dose as intact Didanosine when Didanosine was given under fasting conditions and with food, respectively. The values of Cmax, AUC0-infinity, and %UR were significantly lower for subjects who received Didanosine with food compared with those observed for the fasted subjects. The time to reach Cmax, mean residence time, elimination half-life, and renal clearance remained essentially the same between the two treatments. The results from this study indicated that the rates of absorption and elimination were not affected by the presence of food; however, the extent of absorption, as indicated by AUC0-infinity and %UR, was reduced significantly in the presence of food. It is recommended that Didanosine be administered under fasting conditions.
Lawrence R Crane - One of the best experts on this subject based on the ideXlab platform.
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zidovudine alone or in combination with Didanosine or zalcitabine in hiv infected patients with the acquired immunodeficiency syndrome or fewer than 200 cd4 cells per cubic millimeter
The New England Journal of Medicine, 1996Co-Authors: Louis D Saravolatz, Carla Pettinelli, Dean L Winslow, Gary Collins, James S Hodges, Daniel S Stein, Norman Markowitz, Randall R Reves, Mark O Loveless, Lawrence R CraneAbstract:Background We compared two combinations of nucleosides with zidovudine alone in patients with advanced human immunodeficiency virus (HIV) infection. Methods A total of 1102 patients with the acquired immunodeficiency syndrome or fewer than 200 CD4 cells per cubic millimeter were randomly assigned to receive zidovudine alone or zidovudine combined with either Didanosine or zalcitabine. Disease progression, survival, toxic effects, and the CD4 cell response were assessed. Results After a median follow-up of 35 months, disease progression or death occurred in 62 percent of the 363 patients assigned to zidovudine plus Didanosine, 63 percent of the 367 assigned to zidovudine plus zalcitabine, and 66 percent of the 372 assigned to zidovudine alone (P = 0.24). As compared with zidovudine therapy, treatment with zidovudine plus Didanosine was associated with a relative risk of disease progression or death of 0.86 (95 percent confidence interval, 0.71 to 1.03), and treatment with zidovudine plus zalcitabine was as...
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a comparative trial of Didanosine or zalcitabine after treatment with zidovudine in patients with human immunodeficiency virus infection
The New England Journal of Medicine, 1994Co-Authors: Donald I Abrams, Anne I Goldman, Cynthia A Launer, Joyce A Korvick, James D Neaton, Lawrence R Crane, Michael Grodesky, Steven Wakefield, Katherine Muth, Sandra KornegayAbstract:Background Both Didanosine and zalcitabine are commonly used to treat patients with human immunodeficiency virus (HIV) infection who cannot tolerate zidovudine treatment or who have had disease progression despite it. The relative efficacy and safety of these second-line therapies are not well defined. Methods In this multicenter, open-label trial we randomly assigned 467 patients who previously received zidovudine and had 300 or fewer CD4 cells per cubic millimeter or a diagnosis of the acquired immunodeficiency syndrome (AIDS) to treatment with either Didanosine (500 mg per day) or zalcitabine (2.25 mg per day). Results After a median follow-up of 16 months, disease progression or death occurred in 157 of 230 patients assigned to Didanosine and 152 of 237 patients assigned to zalcitabine, for a relative risk of 0.93 for the zalcitabine group as compared with the Didanosine group (P = 0.56), which decreased to 0.84 (P = 0.15) after adjustment for the CD4 count, Karnofsky score, and presence of AIDS at ba...