Safety Of Nelfinavir Research Articles

1128. Efficacy and Safety of Nelfinavir in Asymptomatic and Mild COVID-19 Patients: A Multicenter, Randomized Controlled Trial

Abstract Background Nelfinavir, an orally administered inhibitor of human immunodeficiency virus protease, inhibited the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. To evaluate the efficacy and safety of nelfinavir, we conducted a randomized controlled trial. Methods Adult patients testing positive for SARS-CoV-2 infection within 3 days were eligible for the study if they had no or mild symptoms of coronavirus disease 2019. Exclusion criteria included the followings: onset of symptoms ≥ 8 days before enrollment; oxygen saturation of 95% or less on room air; and vaccinated patients. Patients were randomly assigned (1:1) to receive oral nelfinavir 750 mg (×3 times daily) combined with standard-of-care or standard-of-care alone. The primary endpoint was the time to clearance of SARS-CoV-2. Saliva was collected every day and viral load was measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Nelfinavir was administered for 14 days. However, the treatment could be discontinued by the decision of investigator, if patients had 2 consecutive negative test results by qRT-PCR. Clinical course and safety information were collected through day 28. The study is registered with the Japan Registry of Clinical Trials (number, jRCT2071200023). Results Between July 2020 and October 2021, 123 patients (63 in the nelfinavir group and 60 in the control group) were enrolled into the study and included in the analysis. The median time to viral clearance was 8.0 (95% confidence interval [CI] 7.0 to 12.0) days in the nelfinavir group and 8.0 (95% CI 7.0 to 10.0) days in the control group without statistically significant difference between the treatment group (hazard ratio 0.815, 95% CI 0.563 to 1.182; P = 0.1870). Adverse events were reported in 47 (74.6%) patients in the nelfinavir group and 20 (33.3%) in the control group. The most common adverse events in the nelfinavir group were diarrhea (49.2%) and nausea (6.3%). Conclusion Nelfinavir did not reduce the time to viral clearance in this setting. Disclosures Shigeru Kohno, n/a, Pfizer: Grant/Research Support|Pfizer: Honoraria Taiga Miyazaki, n/a, Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria.

Pharmacokinetics and Safety of Nelfinavir When Used in Combination with Zidovudine and Lamivudine in HIV-Infected Pregnant Women: Pediatric AIDS Clinical Trials Group (PACTG) Protocol 353

Background: Combination antiretroviral regimens including nelfinavir (NFV) are commonly used in pregnancy. We studied the safety, antiviral effect, and pharmacokinetics of NFV and its M8 metabolite with two dosing regimens in combination with zidovudine (ZDV) and lamivudine (3TC) in HIV-infected pregnant women. Method: HIV-infected pregnant women between 14 and 34 weeks gestation received NFV (Cohort 1: 750 mg tid, n = 10; Cohort 2: 1250 mg bid, n = 23) with ZDV and 3TC. Serial blood sampling for NFV concentrations was performed antepartum (AP) and 6 weeks postpartum (PP). Maternal and cord blood samples were also obtained at delivery. NFV and M8 levels were determined by high-performance liquid chromatography. The pharmacokinetic (PK) target was an extrapolated NFV AUC_0–24 > 30 μg · h/mL. Mothers were followed frequently for potential clinical and laboratory toxicity. Results: Overall, NFV in combination with ZDV and 3TC was well tolerated. The PK target was met in 3/8 AP and 5/7 PP in Cohort 1 and 17/21 AP and 16/17 PP in Cohort 2. When Cohort 2 NFV PK parameters AP and PP were compared, median C_max (3.90 μg/mL vs. 5.01 μg/mL, p < .05) and AUC_0-24 (56.6 vs. 86.8 μg · h/mL, p < .05) were increased PP and oral clearance (Cl/F; 44.2 vs. 28.8 L/h, p < .05) was decreased PP. The average M8/NFV ratio was increased PP compared to AP (0.085 vs. 0.29, p < .001). Placental transfer of NFV was low with a median cord blood:maternal plasma ratio at delivery of 0.05. Maternal mean CD4+ T cell counts increased significantly and plasma HIV-1 RNA levels decreased from entry to delivery and 6 to 12 weeks postpartum. Conclusion: NFV used in combination with ZDV and 3TC was well tolerated in pregnant HIV-infected women and produced a significant improvement in HIV disease parameters. NFV drug exposure is inadequate in most pregnant women receiving 750 mg tid but is much improved with 1250 mg bid. NFV crosses the placenta poorly. The AP increase in NFV oral clearance and decrease in M8/NFV ratio suggest that CYP3A activity increases relative to CYP2C19 activity during pregnancy.

Significant Decrease in Nelfinavir Systemic Exposure After Omeprazole Coadministration in Healthy Subjects

To assess the effect of omeprazole on the multiple-dose (steady-state) pharmacokinetics and safety of nelfinavir, and to evaluate the safety and tolerability of nelfinavir when administered alone and with omeprazole. Open-label, two-period, single-fixed-sequence study. Clinical research unit of a large, teaching hospital. Twenty healthy volunteers (mean age 26 +/- 9 yrs, range 18-48 yrs). Intervention. Subjects received nelfinavir 1250 mg every 12 hours for 4 days (period 1). After a 7-day washout period, subjects were coadministered nelfinavir 1250 mg every 12 hours and omeprazole 40 mg every 24 hours for 4 days (period 2). The pharmacokinetics of nelfinavir and its active metabolite M8 were determined on day 4 of both periods. Plasma samples were assayed by a high-performance liquid chromatography-ultraviolet method for nelfinavir and M8 concentrations, and noncompartmental pharmacokinetic analysis was performed by using analytical software. In the presence of omeprazole, nelfinavir area under the concentration-time curve over the dosing interval (AUC(tau)), maximum observed plasma concentration (C(max)), and minimum observed plasma concentration (C(min)) were reduced by an average of 36%, 37%, and 39%, respectively, relative to administration of nelfinavir alone. The AUC(tau), C(max), and C(min) of M8 were reduced by an average of 92%, 89%, and 75%, respectively. The slopes of the terminal elimination phase of nelfinavir and M8 plasma concentration-time curves were similar between treatments. Nelfinavir was well tolerated when administered alone and when coadministered with omeprazole. The observed reduction in the systemic exposure to both nelfinavir and its active metabolite M8 after coadministration with omeprazole could result in loss of virologic control and potential emergence of drug resistance. Hence, omeprazole should not be coadministered to patients taking nelfinavir.

A Randomized Clinical Trial Comparing Nelfinavir Or Nevirapine Associated to Zidovudine/Lamivudine in HIV-Infected Naive Patients (The Combine Study)

Non-nucleoside reverse transcriptase inhibitor-containing regimens may be a valid alternative to protease inhibitor-containing regimens for initial antiretroviral therapy, but to date few studies comparing these two strategies have been performed. To evaluate the efficacy and safety of nelfinavir or nevirapine associated to zidovudine/lamivudine in HIV-infected naive patients. Randomized, open-label, multicentre trial. Twelve centres in Spain (9) and Argentina (3). One hundred and forty-two HIV-infected naive patients without AIDS. Patients received combivir (zidovudine 300 mg/lamivudine 150 mg, twice-daily) plus either nelfinavir (1250 mg) twice-daily (zidovudine/lamivudine/nelfinavir, n=70) or nevirapine (200 mg) twice-daily (zidovudine/lamivudine/nevirapine, n=72), and were followed for 12 months. The primary endpoint was the proportion of patients with a plasma HIV-1 RNA (pVL) of less than 200 copies/ml by PCR at 12 months. pVL of less than 20 copies/ml (PCR), changes in CD4 counts, clinical progression and adverse events were also evaluated. Efficacy was assessed using intent-to-treat (ITT) (missing=failure) and on-treatment analysis. At 12 months in the ITT analysis the proportion of patients with pVL below 200 copies/ml was 60% (95% CI 48.5-71.5) in the zidovudine/lamivudine/nelfinavir arm and 75% (95% CI 65-85) in the zidovudine/lamivudine/nevirapine arm (P=0.06), and the proportion below 20 copies/ml was 50% (95% CI 38.3-61.7) and 65% (95% CI 54.2-76.2), respectively (P=0.06). No differences were found when comparing the subgroup of patients with baseline pVL of more than 100,000 copies/ml. A gain of +173 and +162 CD4 cells/mm3, respectively, was observed. Zidovudine/lamivudine/nelfinavir was discontinued in 21% of patients, and zidovudine/lamivudine/nevirapine in 25%, due to toxicity (P>0.2). Our results suggest that zidovudine/lamivudine/nevirapine is at least as effective as zidovudine/lamivudine/nelfinavir as first-line therapy for HIV disease.