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Biomedical subjects

P P Koopmans

Publications and source records attributed to P P Koopmans.

At least 19 recordsLinked to original sources
PubMed2004

Effect of efavirenz treatment on the pharmacokinetics of nelfinavir boosted by ritonavir in healthy volunteers.

AIMS: A once-daily (q.d.) nucleoside-sparing regimen can prevent mitochondrial toxicity, overcome viral resistance and improve compliance. In the present study the effect of efavirenz on the pharmacokinetics and tolerability of once-daily nelfinavir/ritonavir was evaluated in healthy subjects. METHODS: This was a multiple-dose, open-label, single-group, two-period study in 24 healthy subjects. Each received from days 1-10 (period 1): 1875 mg nelfinavir plus 200 mg ritonavir q.d. with a 300-kcal snack. During days 11-20 (period 2) efavirenz 600 mg q.d. was added to the regimen. Blood samples were collected up to 24 h after dosing on days 10 (period 1) and 20 (period 2). High-performance liquid chromatography methods were used for the determination of the concentrations of all compounds. The main pharmacokinetic parameters were calculated using noncompartmental methods. RESULTS: All subjects completed the study. After the first period mean nelfinavir AUC(0-24 h), C(max) and C(24) were 49.6 mg h(-1) l(-1), 5.0 mg l(-1) and 0.37 mg l(-1), and the sum of nelfinavir plus its active metabolite M8 C(24) was 0.83 mg l(-1). The relative bioavailability, expressed as a geometric mean ratio (90% confidence interval) for nelfinavir AUC(0-24 h), C(max) and C(24) of period 2 compared with period 1 was: 1.30 (1.21, 1.40), 1.29 (1.19, 1.40) and 1.48 (1.32, 1.66). The sum of nelfinavir and M8 C(24) in period 2 was 0.99 mg l(-1), an increase of 19%. No serious adverse events occurred. CONCLUSIONS: The studied regimens were well tolerated. Nelfinavir/ritonavir given together with efavirenz resulted in a 48% higher mean C(24) concentration for nelfinavir, and the sum of nelfinavir and M8 C(24) concentrations was 0.99 mg l(-1). Efavirenz exposure in this study was similar to that reported previously, and therefore can be used effectively in combination with ritonavir and nelfinavir.

Alkynes↗
PubMed2004

Pharmacokinetics of adjusted-dose lopinavir-ritonavir combined with rifampin in healthy volunteers.

Coadministration of lopinavir-ritonavir, an antiretroviral protease inhibitor, at the standard dose (400/100 mg twice a day [BID]) with the antituberculous agent rifampin is contraindicated because of a significant pharmacokinetic interaction due to induction of cytochrome P450 3A by rifampin. In the present study, two adjusted-dose regimens of lopinavir-ritonavir were tested in combination with rifampin. Thirty-two healthy subjects participated in a randomized, two-arm, open-label, multiple-dose, within-subject controlled study. All subjects were treated with lopinavir-ritonavir at 400/100 mg BID from days 1 to 15. From days 16 to 24, the subjects in arm 1 received lopinavir-ritonavir at 800/200 mg BID in a dose titration, and the subjects in arm 2 received lopinavir-ritonavir at 400/400 mg BID in a dose titration. Rifampin was given at 600 mg once daily to all subjects from days 11 to 24. The multiple-dose pharmacokinetics of lopinavir, ritonavir, and rifampin were assessed. Twelve of 32 subjects withdrew from the study. For nine subjects lopinavir-ritonavir combined with rifampin resulted in liver enzyme level elevations. Pharmacokinetic data for 19 subjects were evaluable. Geometric mean ratios for the lopinavir minimum concentration in serum and the maximum concentration in serum (C(max)) on day 24 versus that on day 10 were 0.43 (90% confidence interval [CI], 0.19 to 0.96) and 1.02 (90% CI, 0.85 to 1.23), respectively, for arm 1 (n = 10) and 1.03 (90% CI, 0.68 to 1.56) and 0.93 (90% CI, 0.81 to 1.07), respectively, for arm 2 (n = 9). Ritonavir exposure increased from days 10 to 24 in both arms. The geometric mean C(max) of rifampin was 13.5 mg/liter (day 24) and was similar between the two arms. Adjusted-dose regimens of lopinavir-ritonavir in combination with therapeutic drug monitoring and monitoring of liver function may allow concomitant use of rifampin.

Adult↗
PubMed2004

Highly active antiretroviral therapy for HIV infection: lessons for the future.

HIV-related morbidity and mortality has been greatly reduced since the introduction of highly active antiretroviral therapy. Issues regarding the patient, the virus, the drugs and the treatment team are discussed. HIV treatment remains complex with a rapidly changing field of possibilities and views, and should therefore be limited to specialised centres.

Antiretroviral Therapy, Highly Active↗
PubMed2003

[Enfuvirtide, the first representative of a new class of drugs for the treatment of HIV infection : HIV fusion inhibitors].

In March 2003, enfuvirtide was approved in the USA and the European Union for the treatment of patients with HIV infection who have experienced failure or intolerable side effects of treatment with at least one representative of each antiretroviral drug class. Enfuvirtide has a new mode of action: it binds to the viral envelope glycoprotein 41 that is involved in the fusion of the virus to the membrane of the CD4 T cell. In two large phase III studies, 90 mg of enfuvirtide administered twice daily subcutaneously in addition to a background treatment of other antiretroviral drugs, had a significant favourable effect on both the plasma viral load (decrease) and the CD4 counts (increase) compared to the background treatment alone. Disadvantages of treatment with enfuvirtide are its subcutaneous administration (98% of the patients had local adverse reactions) and the high costs involved (1500 euro per patient per month).

Anti-HIV Agents↗
PubMed2003

[Tuberculosis and HIV coinfection in three patients: the possibilities for simultaneous treatment].

Three patients received simultaneous treatment for tuberculosis and HIV: a 23-year-old woman and a 33-year-old man who were asylum seekers from Africa and a 45-year-old woman who was an intravenous drug addict. During the treatment with antiretroviral and anti-tuberculous drugs, several problems arose: drug interactions (between rifampicine and protease inhibitors/non-nucleoside reverse transcriptase inhibitors), side effects, non-compliance and immune reconstitution reactions. These problems were solved either by temporary withdrawal of the medication or by substituting other drugs. There are a number of possible treatment strategies that minimise the risks. Despite the potential problems, in patients with advanced HIV infection, antiretroviral treatment should not be delayed until after the end of the tuberculosis treatment.

Adult↗
PubMed2003

Pharmacokinetics, food intake requirements and tolerability of once-daily combinations of nelfinavir and low-dose ritonavir in healthy volunteers.

AIMS: This study was performed to evaluate the steady-state pharmacokinetics, food intake requirements and short-term tolerability of once-daily combinations of nelfinavir and low-dose ritonavir. METHODS: Twenty-seven healthy volunteers were randomized over three groups to receive a once-daily regimen of nelfinavir/ritonavir 2,000/200 mg (group 1), 2,000/400 mg (group 2) or 2,500/200 mg (group 3) with food for 14 days. Pharmacokinetic parameters for nelfinavir and its active metabolite M8 were assessed on study days 15 and 16, after administration of the regimens with a full (610 kcal) or light (271 kcal) breakfast, respectively. RESULTS: Pharmacokinetic data were evaluable for eight volunteers in group 1, eight in group 2 and four in group 3. Administration of nelfinavir/ritonavir with a full breakfast resulted in geometric mean (GM) nelfinavir AUC(24h) values of 76.8, 51.3, and 61.9 h*mg/l in group 1, 2 and 3, respectively. GM 24-h Cmin concentrations of nelfinavir were 0.76 mg l(-1), 0.43 mg l(-1) and 0.47 mg l(-1), respectively. Co-administration of ritonavir increased M8 concentrations more than nelfinavir concentrations, resulting in GM AUC(24h) and Cmin values for nelfinavir plus M8 that were higher than or comparable to reference values for the approved regimen of nelfinavir (1,250 mg BID without ritonavir). In the 2,000/200 mg group, seven out of eight subjects had a Cmin value of nelfinavir plus M8 above a threshold of 1.0 mg l-1. Administration of the combinations with a light breakfast resulted in significant decreases in the AUC(24h) and Cmin of nelfinavir and nelfinavir plus M8, compared with intake with a full breakfast. For the Cmin of nelfinavir plus M8, the GM ratio (light/full breakfast) was 0.76 (90% confidence interval 0.67-0.86, participants from all groups combined). Short-term tolerability was satisfactory, apart from a higher than expected incidence of mild rash (12%). CONCLUSIONS: Administration of nelfinavir in a once-daily regimen appears feasible. A nelfinavir/ritonavir 2,000/200 mg combination appears appropriate for further evaluation. Once-daily nelfinavir/ritonavir should be taken with a meal containing at least 600 kcal.

Adolescent↗
PubMed2002

[Oral fluoropyrimidines registered for the treatment of metastatic colorectal carcinoma: a possible gain].

Up until now the standard treatment for metastasized colorectal carcinoma has been fluorouracil (5-FU) in combination with folonic acid in low doses administered intravenously, even after the recent registration of a number of new intravenously administered cytostatics, such as irinotecan and oxaliplatin. Meanwhile there are oral alternatives for 5-FU: capecitabine and the combination of tegafur and uracil with folonic acid. In four randomised studies it was shown that these drugs were globally just as effective as the combination of 5-FU with folonic acid (in accordance with the 'Mayo Clinic' scheme). There was no survival advantage for the oral drugs compared to 5-FU with folonic acid. Compared to 5-FU and folonic acid the use of capecitabine or tegafur-uracil-folonic acid was associated with less toxic effects; however, there were differences in the side effects profile between the oral drugs and 5-FU (more hand-foot syndrome for capecitabine and less (symptomatic) leucopenia for tegafur-uracil-folonic acid). An examination of the serious side effects (grade 3 and 4) revealed that the total incidence was generally comparable. These data, together with the ease of oral administration, form the basis for the registration of capecitabine and tegafur-uracil-folonic acid. The definitive place of these drugs in the treatment of metastasized colorectal carcinoma is not yet clear.

Administration, Oral↗
PubMed2002

Saquinavir soft-gel capsules (Fortovase) give lower exposure than expected, even after a high-fat breakfast.

BACKGROUND: The soft-gel capsule (sgc) of saquinavir has been developed in order to improve the poor oral bioavailability of the original hard-gel capsules. However, in a Dutch study population using saquinavir-sgc plasma levels were lower than expected. We hypothesised that this was caused by differences in the amount of fat in the meals of the study populations. METHODS: 8-h steady-state plasma curves after observed ingestion of 1200 mg saquinavir-sgc were recorded, concomitantly with a normal breakfast (600 kcal, 33% fat) on the first day, and a high-fat breakfast (1040 kcal, 54% fat) on the second day. Additionally, a comparison was made between saquinavir hard-gel capsules and saquinavir-sgc with or without grapefruit juice (n = 1). Furthermore, a comparison between saquinavir-sgc and ritonavir + saquinavir-sgc 400/400 mg bid was made (n = 1). RESULTS: Although saquinavir exposure was improved by fat, grapefruit juice or ritonavir, exposure to saquinavir for all recorded curves was lower than expected. A large proportion of trough concentrations was below the efficacy threshold. CONCLUSION: Intake of squinavir-sgc with high-fat meals or grapefruit juice may improve the pharmacokinetic profile. However, plasma concentrations may then still be lower than expected and insufficient for good antiviral efficacy. Probably the only way to reach adequate saquinavir concentrations is by combining saquinavir with ritonavir.

Adult↗
PubMed2001

Analysis of variation in plasma concentrations of nelfinavir and its active metabolite M8 in HIV-positive patients.

OBJECTIVE: To characterize sources of variation in plasma concentrations of nelfinavir and its active metabolite M8 and to evaluate the use of therapeutic drug monitoring for nelfinavir treatment. METHODS: Plasma samples and patient's characteristics were obtained from outpatient clinic. Differences between groups of patients were studied by comparing the observed plasma concentrations with the corresponding concentration on a pharmacokinetic population curve based on median plasma levels. RESULTS: Plasma samples (618) were available from 355 patients taking 1250 mg nelfinavir twice daily. The median ratio between M8 and nelfinavir concentrations was 0.29. This ratio appeared to be independent of the time after ingestion. Statistically significantly lower M8 concentrations were found in Black and Asian patients, or when comedication with CYP3A4 inducers was used. Coadministration of CYP2C19 inhibitors, such as omeprazole, decreased the median M8/nelfinavir ratio. Nevertheless, nelfinavir concentrations and summed concentrations of nelfinavir and M8 were only marginally affected in these patients. Diarrhoea was identified as a cause for lower nelfinavir concentrations, without changing the M8/nelfinavir ratio. In a number of patients with suspected therapy failure or intoxication, abnormal nelfinavir plasma concentrations were found. Dose adjustments based on nelfinavir plasma levels were helpful in a number of patients. CONCLUSION: This study shows that the total concentration of nelfinavir and M8 together is not significantly influenced when variation in M8 levels occurs. Consequently, measuring M8 concentrations in addition to nelfinavir concentrations is not required for the purpose of therapeutic drug monitoring for this drug.

Adolescent↗
PubMed2001

[Therapy of HIV infection: how early and how intensive?].

Three men aged 53, 25 and 34 years and 2 women aged 39 and 34 years with HIV infection had different courses with and without highly active antiretroviral therapy (HAART). Medication regimes were often complicated and adverse events occurred frequently, which led to adjustment of treatment. Since the introduction of HAART for treatment of HIV infection, a tremendous progress has been achieved, resulting in reduction of HIV related events and in reduction of fatality due to AIDS. However, besides the positive effects of this therapy, there is also a negative side of HAART. In addition to the complexity and adverse events, the medication has to be taken lifelong while non-compliance might result in resistance-mutation. If HAART might be indicated, it is necessary to weigh the pros and contras before starting with medication.

Adult↗
PubMed2001

The effect of fluconazole on ritonavir and saquinavir pharmacokinetics in HIV-1-infected individuals.

AIMS: To study the effect of fluconazole on the steady-state pharmacokinetics of the protease inhibitors ritonavir and saquinavir in HIV-1-infected patients. METHODS: Five subjects treated with saquinavir and three with ritonavir received the protease inhibitor alone (saquinavir 1200 mg three times daily, ritonavir 600 mg twice daily) on day 1, and the same protease inhibitor in combination with fluconazole (400 mg on day 2 and 200 mg on days 3 to 8). Pharmacokinetic parameters were determined on days 1 and 8. RESULTS: In the saquinavir group, the median increase in the area under the plasma concentration vs time curve was 50% from 1800 microg l(-1) h to 2700 microg l(-1) h (P = 0.04, median increase: 900 microg l(-1) h; 2.5 and 97.5 percentile: 500-1300), and 56% for the peak concentration in plasma (from 550 to 870 microg l(-1), P = 0.04; median increase: 320 microg l(-1) h, 2.5 and 97.5 percentile: 60-450 microg l(-1)). In the ritonavir group, there were no detectable changes in the pharmacokinetic parameters on addition of fluconazole. CONCLUSIONS: Because of the favourable safety profile of saquinavir, dose adjustments are probably not necessary with concomitant use of fluconazole, as is the case for ritonavir.

Administration, Oral↗
PubMed2000

Dose-finding study of a once-daily indinavir/ritonavir regimen.

In antiretroviral therapy, to improve compliance the need is increasing to develop regimens that combine potency and safety with convenient dosing. The objective of our study was to find a once-daily dosing regimen of a HIV-protease inhibitor, indinavir (IDV), by combining it with ritonavir (RTV). In the study, 12 healthy volunteers took a single IDV dose of 800 mg on day 1. Plasma and urine sampling was done for 12 hours. From day 2 to day 21, participants took RTV liquid 200 mg (group A) or 400 mg (group B) once daily. Repeated pharmacokinetic sampling was performed over the course of 24 hours, after single doses of indinavir 400 mg (day 15), 800 mg (day 18), and 1200 mg (day 21). The best dosage regimen in this pharmacokinetic study was selected based on efficacy and tolerability criteria. The study comprised 10 male and 2 female healthy volunteers, mean age, 25 years (range, 18-50 years), mean weight, 70 kg (range, 52-83 kg). One male participant discontinued on day 8 due to influenza. All other participants completed the study without the occurrence of serious adverse events. RTV inhibited indinavir plasma clearance by 51% to 70%, leading to increased and prolonged IDV exposure. Renal clearance was influenced by the addition of RTV and dosage increments of IDV. The efficacy criterion was best fulfilled by 1200 mg IDV/400 mg RTV, whereas this combination performed most poorly on tolerability criteria. Based on the single dose data, a once-daily regimen of IDV with a low dose of RTV is possible. The best dosage regimen to start with among those studied here appears to be 1200 mg IDV/400 mg RTV, which could be decreased at steady state to 800 IDV/400 RTV or 1200 IDV/200 RTV if toxicity occurs. Steady-state pharmacokinetic data of once-daily IDV/RTV regimens in HIV-infected patients are warranted.

Adolescent↗
PubMed2000

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 degrees 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.

Administration, Oral↗