Pharmacokinetics of PREZISTA

Summary

• In the ARTEMIS study, plasma concentrations of darunavir (DRV) in patients receiving PREZISTA/ritonavir (PREZISTA/r) 800/100 mg once daily (QD) were consistently above the in-vitro protein-binding corrected median effective concentration (EC₅₀) for wild-type virus (55 ng/mL).¹
• The median DRV minimum concentration (C_0h) exceeded the EC₅₀ for protease inhibitor (PI)-resistant virus (550 ng/mL) for each treatment group in the pooled POWER 1 and 2 studies and in both arms of the ODIN study.^2,3
• The EC₅₀ for PI-resistant virus (550 ng/mL) was exceeded in all patients in the POWER 3, TITAN, and GRACE studies, all of whom received PREZISTA/r 600/100 mg twice daily (BID).^4-6
• No direct relationship between DRV pharmacokinetics (PK) and safety or efficacy was observed in the ARTEMIS, ODIN, TITAN, GRACE, and POWER 1, 2, and 3 studies.^1-6

• Lloret-Linares et al (2018)⁷ conducted a prospective, single-center study to compare the steady state plasma concentrations of DRV in normal and overweight human immunodeficiency virus (HIV) infected adult patients treated with PREZISTA/r 800/100 mg QD. DRV concentrations tended to be higher in patients with body mass index (BMI) ≥25 kg/m² than in patients with BMI <25 kg/m² (2896.7±1689 vs 2091.9±1038, respectively, P=0.09) and was positively correlated with fat mass (r=0.32, P=0.02).
• Calza et al (2017)⁸ conducted an observational, open-label study in HIV-1 infected patients treated with PREZISTA/r 800/100 mg QD plus emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) 200/300 mg QD. The geometric mean (GM) plasma trough concentration (C_trough) of DRV was significantly higher among patients aged ≥60 years (older patients) than among patients aged ≤40 years (younger patients) (2209 ng/mL [139%] vs 1876 ng/mL [162%], respectively; geometric mean ratio [GMR], 1.56; 95% confidence interval [CI], 1.22-1.88; P=0.004).
• Tyrberg et al (2021)⁹ conducted a cross-sectional study to evaluate the differences in steady state concentrations of DRV, atazanavir (ATV), or efavirenz (EFV) following the administration of DRV/r 800/100 mg, ATV/r 300/100 mg, or EFV 600 mg QD in HIV-1 infected patients aged ≥65 years (study group, n=100) and ≤49 years (control group, n=99). Compared with the control group (n=30), DRV steady-state concentrations were significantly higher in the study group (n=25; P=0.047).
• Tsirizani et al (2024)¹⁰ presented a PK substudy within the CHAPAS-4 trial, comparing DRV exposure in children with HIV to adults after once-daily PREZISTA/r treatment. Children had slightly higher area under the concentration-time curve from 0 to 24 hours (AUC_0-24h) and maximum plasma concentration (C_max) values than adults, but their C_trough levels were similar to adult reference values.

clinical data

Treatment-Naïve Patients

ARTEMIS Study

The ARTEMIS (AntiRetroviral Therapy with TMC114 ExaMined In naïve HIV-1 infected Subjects) study was a randomized, controlled, open-label, 192-week phase 3 study comparing PREZISTA/r 800/100 mg QD versus either lopinavir/r (LPV/r) 800/200 mg QD or LPV/r 400/100 mg BID in treatment-naïve patients. All patients received a fixed-dose background regimen of FTC/TDF 200/300 mg QD (N=689).¹¹

Study Design/Methods

• Sparse blood sampling for PK/pharmacodynamic (PD) analysis was carried out at weeks 4, 8, 24, and 48 in DRV/r patients.¹

PK/PD Results

• PK data were available for 335 patients (Figure: Exposure Estimates for DRV 800 mg QD).
• Median (range) DRV population PK parameters:
  • Area under the concentration-time curve from t=0-24h (AUC_0-24h) (ng·h/mL)=87,854 (45,000-219,240)
  • Trough concentration (C_0h) (ng/mL)=2041 (368-7242)

• C_trough was consistently above the EC₅₀ for wild-type virus (55 ng/mL) in all patients.
  • Median C_0h was 37-fold greater than the EC₅₀.
• No relationship was observed between DRV exposure (AUC_24h and C_0h) and virologic response (VR) at week 48.
  • Mean reductions in viral load (VL) and the proportion of patients achieving VL <50 copies/mL were consistently similar across the range of AUC_24h and C_0h values measured through week 48.
• No relationship was observed between DRV exposure (AUC_24h and C_0h) and the occurrence of rash, nervous system, psychiatric, cardiac, gastrointestinal (GI), liver, lipid, and glucose-related adverse events (AEs).

Effect of Different Covariates on DRV/r PK Exposure

• Female patients had higher DRV exposures compared to male patients.¹²
  • Mean AUC_24h was 96,364 ng·h/mL and 84,754 ng·h/mL in female and male patients, respectively.
  • Mean C_0h was 2288 ng/mL and 1918 ng/mL in female and male patients, respectively.
• Mean DRV exposure and C_trough was lowest in Asian patients compared to other ethnic subgroups.¹²
  • Mean AUC_24h and C_0h were 79,824 ng·h/mL and 1763 ng/mL, respectively.
• The differences observed in DRV exposure with respect to gender and race were not considered clinically relevant.¹²
• Age, body weight, and hepatitis B and/or C coinfection had no effect on DRV exposure.¹²

Treatment-Experienced Patients

ODIN Study

The ODIN (Once-daily Darunavir In treatment-experieNced patients) study was a randomized, open-label, parallel assignment, 48-week phase 3 study comparing PREZISTA/r 800/100 mg QD or PREZISTA/r 600/100 mg BID, each in combination with an optimized background regimen (OBR) consisting of ≥2 investigator-selected nucleoside reverse transcriptase inhibitors (NRTIs), in 590 treatment-experienced patients with no DRV resistance-associated mutations (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, and L89V).¹³

Study Design/Methods

• Sparse blood sampling for PK/PD analysis was carried out at weeks 4, 8, 24, and 48.³

PK/PD Results

• Data were available for 280 patients in the QD arm and 278 patients in the BID arm (Table: DRV PK at Week 48 in the ODIN Study).

• C_0h and AUC_24h of DRV were lower with QD dosing than with BID dosing.
• The entire range of plasma concentrations for DRV QD and BID were above the EC₅₀ (55 ng/mL) for wild-type HIV (adjusted for protein binding).
• No clinically relevant relationships between DRV PK and efficacy were found.
• No relationships between DRV PK and laboratory lipid abnormalities or rash, cardiac, GI, liver, lipid, or glucose-related AEs were found.

Effect of Different Covariates on DRV PK Exposure

• Age, body weight, and hepatitis coinfection status did not affect DRV exposure.
• Differences in DRV exposure with respect to gender and race were not considered to be clinically relevant.
  • Mean DRV AUC_24h was higher in females (QD regimen: 94,780 ng·h/mL; BID regimen: 111,744 ng·h/mL) than in males (QD regimen: 84,031 ng·h/mL; BID regimen: 107,810 ng·h/mL).
  • DRV exposure was highest in blacks, followed by Caucasians and Hispanics, and lowest in Asians.

TITAN Study

The TITAN (TMC114/r In Treatment-experienced pAtients Naive to lopinavir) study was a randomized, controlled, open-label, 96-week phase 3 study comparing PREZISTA/r 600/100 mg BID or LPV/r 400/100 mg BID, each in combination with an investigator-selected OBR that consisted of ≥2 antiretrovirals (NRTIs ± non-nucleoside reverse transcriptase inhibitors [NNRTIs]), in treatment-experienced, LPV-naïve patients (N=595).¹⁴

Study Design/Methods

• Sparse blood sampling for PK analysis was carried out at weeks 4, 8, 24, and 48 in PREZISTA/r patients (n=285).⁵

PK/PD Results

• Median (range) C_0h was 3306 (1517-13,198) ng/mL, which consistently exceeded the EC₅₀ value for PI-resistant HIV-1 strains (550 ng/mL).
• Median (range) 12-hour area under the plasma concentration-time curve (AUC_12h): 55,816 (32,437-177,680) ng·h/mL.
• No relationship was observed between DRV exposure (AUC_12h, C_0h) and VR (VL <400 copies/mL).
• No relationship was observed between the incidence of AEs of interest experienced by patients and DRV exposure.

Effect of Different Covariates on DRV PK Exposure

• DRV AUC_12h was not affected by coadministration of nevirapine or EFV, age, body weight, or hepatitis B or C coinfection.¹⁵
• The differences observed in DRV exposure (AUC_12h) with respect to gender and race were not considered to be clinically relevant.¹⁵
  • DRV AUC_12h was 8% higher in females (59,072 ng·h/mL) compared to males (54,547 ng·h/mL).
  • DRV exposure was highest in blacks (62,280 ng·h/mL) and lowest in Asian/Orientals (45,749 ng·h/mL).
• Patients with higher baseline alpha 1-acid glycoprotein (AAG) levels experienced higher exposure to DRV compared to those with lower baseline AAG levels.¹⁵
  • Differences in exposure may be related to the high binding affinity of DRV to AAG protein.

GRACE Study

The GRACE (Gender, Race And Clinical Experience) study was an open-label, multicenter, 48-week phase 3b study which evaluated gender and race differences in the efficacy, safety, PK, and tolerability of PREZISTA/r 600/100 mg BID plus an OBR in treatment-experienced men (n=142) and women (n=287).¹⁶

Study Design/Methods

• PK analysis was conducted using the following 2 sampling methods:
  • Sparse PK sampling was performed for DRV in all patients at weeks 4, 8, 24, and 48.
  • Intensive PK sampling was performed for DRV/r in a subset of patients at weeks 4, 24, and 48.
    • At each of the timepoints, a sample was collected 15 minutes predose and 1, 2, 3, 4, 6, 9, and 12 hours postdose.
• Relationship of DRV PK with efficacy and safety was assessed at week 48.

PK Substudy Results

• Sparse PK sampling was undertaken in 376 patients:
  • Women 66% (n=248); black 60% (n=226); Hispanic 22% (n=84).
• Intensive PK sampling was undertaken in 37 patients:
  • Women (n=25); black (n=25); Hispanic (n=10); Caucasian (n=2).

PK — Sparse Sampling

• Based on the PK data available, the median (range) DRV AUC_12h and C_0h were 60,642 (26,117-128,790) ng·h/mL and 3624 (931-9570) ng/mL, respectively.
  • DRV C_trough exceeded the EC₅₀ for resistant virus (550 ng/mL) for all patients (median C_0h= 6.5×EC₅₀).

PK — Intensive Sampling

• The plasma concentrations of DRV/r did not show a time-dependent relationship over 48 weeks.
• DRV/r exposures were comparable to population PK data.

Effect of Different Covariates on DRV PK Exposure

• Based on univariate analysis, DRV PK did not differ between women and men or by ethnic subgroups.
• Based on multivariate analysis, higher DRV exposure was statistically correlated with female gender and age; however, these were not considered clinically relevant (as seen in the univariate analysis).
• No relationship was observed between DRV AUC_12h or C_0h and change in VL from baseline to week 48, the proportion of patients that achieved VL <50 copies/mL, or incidence of AEs such as rash, cardiac, GI, liver, glucose, nervous system, or psychiatric-related disorders.

POWER 1, 2, and 3 Studies

The POWER 1, POWER 2, and POWER 3 studies were 144-week phase 2b studies that evaluated the efficacy and safety of PREZISTA/r in highly treatment-experienced HIV-1 infected patients.^17-19

Study Design/Methods

• The POWER 1 and 2 studies were randomized, controlled, partially blinded studies evaluating the safety and efficacy of various dosing regimens of PREZISTA/r (400/100 mg QD, 800/100 mg QD, 400/100 mg BID, or 600/100 mg BID) in comparison with other PIs, each in combination with an OBR.^17,18
• POWER 3 was an analysis of 2 open-label, single-arm trials evaluating the efficacy and safety of PREZISTA/r 600/100mg bid plus an OBR.^20,21
• PK data for the POWER 1, 2, and 3 studies were based on population PK modeling on sparse samples.

PK Results

• No direct relationship was observed between DRV PK and VR or AEs.

Effect of Body Weight and Composition

Lloret-Linares et al (2018)⁷ conducted a prospective, single-center study in France to compare the steady-state PK of DRV in normal and overweight HIV infected adult patients receiving PREZISTA/r 800/100 mg QD combined with at least 2 NRTIs and determined the relationship between concentrations and fat mass.

Study Design/Methods

• Patients received the PREZISTA/r QD regimen for at least 6 months prior to study enrollment.
• Blood samples were collected 24 hours (±1 hour) after the last PREZISTA/r dose.

PK Results

• A total of 48 patients were enrolled in the study.
• DRV concentrations tended to be higher in patients with BMI ≥25 kg/m² (P=0.09) and was positively correlated with fat mass (r=0.32, P=0.02). Clusters of differentiation (CD)4+ T cell count and the percentage of patients with a VL of <20 copies/mL did not differ according to the BMI group (Table: Antiretroviral Drug Concentration and Immune Status of Patients Treated With DRV With Respect to BMI).
• According to BMI quartiles, the DRV concentrations were:
  • BMI 17.4-18.3 (n=4): 2174.0±864.2 µg/L
  • BMI 18.5-24.8 (n=23): 2077.6±1082 µg/L
  • BMI 25.3-29.9 (n=14): 2701.1±1410.3 µg/L
  • BMI 30.3-35.4 (n=7): 3287.7±223.1 µg/L
• In a subgroup analysis, the effect of fat mass on serum concentrations was significant in the 52.1% of patients from Sub Sahara Africa (r=0.4, P=0.04).

Older vs Younger Patients

Calza et al (2017)⁸ conducted a observational, open-label study to evaluate the plasma concentrations of DRV following administration of PREZISTA/r 800/100 mg QD in combination with FTC/TDF in HIV-1 infected patients ≥60 years old (older patients; n=21) in comparison with those ≤40 years old (younger patients; n=25).

Study Design/Methods

• The plasma C_trough of DRV/r were assessed at steady state (>4 weeks after the start of treatment).
• Blood samples were obtained before the morning dose and 23-25 hours after the previous morning dose of PREZISTA/r.

PK Results

• The GM plasma C_trough (coefficient of variation [CV%]) of DRV was 2017 ng/mL (145%), and was significantly higher in older patients than in younger patients (Table: DRV Plasma Concentrations in Younger and Older Patients).
• Overall, the mean DRV C_trough (CV%) was significantly higher in female patients (2144 ng/mL; 143%) than in male patients (1991 ng/mL; 128%; GMR 1.48; 95% CI: 1.21-1.89; P=0.041), in patients with BMI <24 kg/m² (2219 ng/mL; 119%) than in those with BMI ≥24 kg/m² (1887 ng/mL; 152%; GMR 1.57; 95% CI: 1.29-1.78; P=0.039), and in patients with albumin concentration <3.5 g/dL (2144 ng/mL; 167%) than in those with albumin concentration ≥3.5 g/dL (1914 ng/mL; 148%; GMR 1.66; 95% CI: 1.26-1.98; P=0.019).
• Similar results were observed with mean ritonavir C_trough levels (data not shown).

Effect of Different Covariates on DRV/r PK Exposure

• Female gender and BMI <24 kg/m² were significantly associated with increased plasma concentrations of DRV (C_trough >2200 ng/mL) by univariate and multivariate analysis.
• Albumin concentration <3.5 g/dL was significantly associated with increased plasma levels of DRV by both analyses (Table: Univariate and Multivariate Logistic Regression Analyses of Factors Associated With Increased Plasma Concentrations of DRV).

Tyrberg et al (2021)⁹ conducted a cross-sectional study to evaluate the differences in steady state concentrations of DRV, ATV, or EFV following the administration of DRV/r 800/100 mg, ATV/r 300/100 mg, or EFV 600 mg QD in HIV-1 infected patients aged ≥65 years (study group, n=100) and ≤49 years (control group, n=99).

Study Design/Methods

• HIV-1 infected patients aged ≥65 years (study group) and ≤49 years (control group) who were on stable treatment with ATV, DRV, or EFV for more than 6 months were included from 4 HIV centers in Sweden.
• Blood samples were collected on the day of inclusion for the measurement of plasma drug levels.
• For the analysis of steady-state drug levels, blood samples were collected between 6 and 36 hours after the last dose of the drug.

PK Results

• Between November 2013 and August 2015, 100 (DRV, n=35; ATV, n=19; EFV, n=46) and 99 patients (DRV, n=37; ATV, n=18; EFV, n=44) were included in the study and control groups, respectively.
• Compared with the control group (n=30), the DRV steady-state concentrations were significantly higher in the study group (n=25; P=0.047).
• Compared with the control group, the GM steady-state concentration was 48% higher in the study group.

Tsirizani et al (2024)¹⁰ presented results of a PK substudy of the PREZISTA/r arm within the CHAPAS-4 trial, which was an open-label, multicenter, randomized trial that evaluated the virological efficacy and PK of boosted protease inhibitors and dolutegravir, in combination with either tenofovir alafenamide fumarate (TAF) or non-TAF-based NRTI backbones. The present study compared exposures between children with HIV (age range, 3-15 years; weight, ≥14 kg) and adults with HIV infection and evaluated the impact of NRTI backbones and other covariates on the PK of DRV.

Study Design/Methods

• PREZISTA/r dosing was based on World Health Organization weight bands (14-19.9 kg, 20-24.9 kg, 25-34.9 kg, and ≥35 kg).
• Children with HIV were treated with once-daily PREZISTA/r at a dose of 600/100 mg (weight, 14-24.9 kg) and 800/100 mg (weight, ≥25 kg), in combination with either TAF/FTC, abacavir/lamivudine (ABC/3TC), or zidovudine/lamivudine (ZDV/3TC).
• They were monitored for a duration of 96 weeks, and blood samples for detailed PK analysis were collected at week 6 at predose and at intervals of 1, 2, 4, 6, 8, 12, and 24 hours after drug intake.

PK Results

• Between January 2019 and March 2021, 59 children were included in the study; the median age was 10.9 years, and the median weight was 26.0 kg.
• In children, the GM (CV%) AUC_0-24h was 94.3 (50%) mg·h/L, and the C_max was 9.1 (35%) mg/L. These were slightly higher than the median (range) adult AUC_0-24h of 69.4 (33.0-88.4) mg·h/L and mean (SD) adult C_max of 5.5 (1.3) mg/L, respectively.
• The GM (CV%) C_trough in children was 1.5 (111%) mg/L, which was similar to the mean (SD) adult C_trough of 1.4 (0.5) mg/L.
• An exponential relationship was found between alpha-1-acid glycoprotein and clearance, with a slope of -0.582 (95% CI, -0.236 to -0.667; P<0.001).
• No significant impact of NRTI backbones on the PK of DRV was observed.

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 18 March 2025.