Tenofovir Plasma Concentration from Preexposure Prophylaxis at the Time of Potential HIV Exposure: a Population Pharmacokinetic Modeling and Simulation Study Involving Serodiscordant Couples in East Africa

Mallayasamy, Surulivelrajan; Chaturvedula, Ayyappa; Fossler, Michael J.; Sale, Mark; Goti, Vineet; Bumpus, Namandjé N.; Marzinke, Mark A.; Hendrix, Craig W.; Haberer, Jessica

doi:10.1128/aac.00446-19

Cited by 4 publications

(2 citation statements)

References 34 publications

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“…For the 46 participants who had tenofovir plasma data that were used in the group-based trajectory modeling (ie, not including those with concurrent tenofovir diphosphate measurements in DBS), participants with plasma concentrations greater than or equal to 40 ng/mL were assigned to the high adherence group. This threshold was selected based on prior studies suggesting that 40 ng/mL reflects recent adherence and that participants with pill coverage of at least 80% had plasma tenofovir concentration greater than 40 ng/mL . Participants with concentrations less than 40 ng/mL were included in the low adherence group.…”

Section: Methodsmentioning

confidence: 99%

HIV Preexposure Prophylaxis With Emtricitabine and Tenofovir Disoproxil Fumarate Among Cisgender Women

Marrazzo,

Tao,

Becker

et al. 2024

JAMA

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ImportanceEmtricitabine and tenofovir disoproxil fumarate (F/TDF) for HIV preexposure prophylaxis (PrEP) is highly effective in cisgender men who have sex with men (MSM) when adherence is high (&gt;4 doses/week). Real-world effectiveness and adherence with F/TDF for PrEP in cisgender women is less well characterized.ObjectiveTo characterize the effectiveness of F/TDF for PrEP and its relationship with adherence in cisgender women.Design, Setting, and ParticipantsData were pooled from 11 F/TDF PrEP postapproval studies conducted in 6 countries that included 6296 cisgender women aged 15 to 69 years conducted from 2012 to 2020. HIV incidence was evaluated according to adherence level measured objectively (tenofovir diphosphate concentration in dried blood spots or tenofovir concentration in plasma; n = 288) and subjectively (electronic pill cap monitoring, pill counts, self-report, and study-reported adherence scale; n = 2954) using group-based trajectory modeling.ExposuresF/TDF prescribed orally once a day. HIV incidence was analyzed in subgroups based on adherence trajectory.Main Outcomes and MeasuresHIV incidence.ResultsOf the 6296 participants, 46% were from Kenya, 28% were from South Africa, 21% were from India, 2.9% were from Uganda, 1.6% were from Botswana, and 0.8% were from the US. The mean (SD) age at PrEP initiation across all studies was 25 (7) years, with 61% of participants being younger than 25 years. The overall HIV incidence was 0.72 per 100 person-years (95% CI, 0.51-1.01; 32 incident HIV diagnoses among 6296 participants). Four distinct groups of adherence trajectories were identified: consistently daily (7 doses/week), consistently high (4-6 doses/week), high but declining (from a mean of 4-6 doses/week and then declining), and consistently low (less than 2 doses/week). None of the 498 women with consistently daily adherence acquired HIV. Only 1 of the 658 women with consistently high adherence acquired HIV (incidence rate, 0.13/100 person-years [95% CI, 0.02-0.92]). The incidence rate was 0.49 per 100 person-years (95% CI, 0.22-1.08) in the high but declining adherence group (n = 1166) and 1.27 per 100 person-years (95% CI, 0.53-3.04) in the consistently low adherence group (n = 632).Conclusions and RelevanceIn a pooled analysis of 11 postapproval studies of F/TDF for PrEP among cisgender women, overall HIV incidence was 0.72 per 100 person-years; individuals with consistently daily or consistently high adherence (4-6 doses/week) to PrEP experienced very low HIV incidence.

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Section: Methodsmentioning

confidence: 99%

HIV Preexposure Prophylaxis With Emtricitabine and Tenofovir Disoproxil Fumarate Among Cisgender Women

Marrazzo,

Tao,

Becker

et al. 2024

JAMA

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“…A series of plasma concentrations can provide a cumulative picture of drug exposure and adherence behaviour for an individual over time. Recently conducted adherence studies focused on HIV, 4,5 tuberculosis 6 and malaria 7 treatments, as well as studies in people taking antipsychotics 8,9 and antidepressants, 10 extend the value of plasma concentration monitoring by conducting simulations from population pharmacokinetic models to determine concentration thresholds or reference ranges outside of which people taking a particular dose could be identified as poorly adherent.…”

Section: Introductionmentioning

confidence: 99%

An allopurinol adherence tool using plasma oxypurinol concentrations

Smith-Diaz

Stocker

Stamp

et al. 2022

Brit J Clinical Pharma

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Aims This study aimed to develop and evaluate an allopurinol adherence tool based on steady‐state oxypurinol plasma concentrations, allopurinol's active metabolite. Methods Plasma oxypurinol concentrations were simulated stochastically from an oxypurinol pharmacokinetic model for allopurinol doses of 100‐800 mg daily, accounting for differences in renal function, diuretic use and ethnicity. For each scenario, the 20th percentile for peak and trough concentrations defined the adherence threshold, below which imperfect adherence was assumed. Predictive performance was evaluated using both simulated low adherence and against data from 146 individuals with paired oxypurinol plasma concentrations and adherence measures. Sensitivity and specificity (S&S), negative and positive predictive values (NPV, PPV) and receiver operating characteristic (ROC) area under the curve (AUC) were determined. The predictive performance of the tool was evaluated using adherence data from an external study (CKD‐FIX). Results The allopurinol adherence tool produced S&S values for trough thresholds of 89‐98% and 76‐84%, respectively, and 90%‐98% and 76‐83% for peak thresholds. PPV and NPV were 79‐84% and 88‐94%, respectively, for trough and 80‐85% and 89‐98%, respectively, for peak concentrations. The ROC AUC values ranged from 0.84 to 0.88 and from 0.86 to 0.89 for trough and peak concentrations, respectively. S&S values for the external evaluation were found to be 75.8% and 86.5%, respectively, producing an ROC AUC of 0.8113. Conclusion A tool to identify people with gout who require additional support to maintain adherence using plasma oxypurinol concentrations was developed and evaluated. The predictive performance of the tool is suitable for adherence screening in clinical trials and may have utility in some clinical practice settings.

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Population Pharmacokinetic Simulations for Dose Optimization of Tenofovir Disoproxil Fumarate in HIV‐Infected Patients with Moderate‐to‐Severe Renal Impairment

Boonpeng,

Singkham,

Wutthikul

et al. 2024

The Journal of Clinical Pharma

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Tenofovir disoproxil fumarate (TDF) requires dosage adjustments from the standard 300 mg once daily to every 48‐96 h for moderate‐to‐severe renal impairment to avoid excessive exposure. However, this extended interval can lead to variable drug exposure and inconvenience. This study aimed to utilize the population pharmacokinetic (PPK) models to optimize TDF dosing regimens for HIV‐infected patients with renal impairment. A systematic literature search was conducted across PubMed, Cochrane Library, and Scopus databases to identify relevant PPK studies of TDF in HIV‐infected patients. From the included studies, the PPK models and associated parameters were extracted. Monte Carlo simulations (n = 2000) were performed to generate concentration–time profiles and derive PK parameters compared against reference ranges. For moderate renal impairment, the TDF 150 mg once‐daily regimen achieved cumulative exposure comparable to the approved 300 mg every‐other‐day regimen. In severe renal impairment, TDF 75‐100 mg administered once daily provided similar cumulative exposure as 300 mg every 72‐96 h regimen while maintaining daily exposure comparable to the standard dose in patients with normal renal function. The approved extended dosing intervals of 72‐96 h exhibited high drug exposure variability, initially resulting in supratherapeutic levels followed by suboptimal levels preceding the subsequent dose administration. In conclusion, administering smaller once‐daily doses of TDF maintains consistent daily drug exposure comparable to the standard dose in patients with normal renal function while reducing variability in drug exposure, potentially mitigating the risk of nephrotoxicity. However, additional clinical studies are required to confirm these findings.

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Tenofovir Plasma Concentration from Preexposure Prophylaxis at the Time of Potential HIV Exposure: a Population Pharmacokinetic Modeling and Simulation Study Involving Serodiscordant Couples in East Africa

Cited by 4 publications

References 34 publications

HIV Preexposure Prophylaxis With Emtricitabine and Tenofovir Disoproxil Fumarate Among Cisgender Women

HIV Preexposure Prophylaxis With Emtricitabine and Tenofovir Disoproxil Fumarate Among Cisgender Women

An allopurinol adherence tool using plasma oxypurinol concentrations

Population Pharmacokinetic Simulations for Dose Optimization of Tenofovir Disoproxil Fumarate in HIV‐Infected Patients with Moderate‐to‐Severe Renal Impairment

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