Lopinavir Cerebrospinal Fluid Steady-State Trough Concentrations in HIV-Infected Adults

Background: The central nervous system may act as a sanctuary site for viral replication in the setting of low antiretroviral penetration. Data on lopinavir cerebrospinal fluid (CSF) trough concentration (Ctrough) values have yet to be reported. Objective: To describe lopinavir CSF Ctrough values and compare them with a measure of HIV susceptibility. Methods: In a prospective, open-label design, HIV-infected adults whose regimen included lopinavir/ritonavir 400/100-mg soft-gel capsules twice daily for at least 4 weeks were enrolled. Each subject had 8 plasma lopinavir concentrations determined over a 12-hour dosing interval and 1 CSF lopinavir Ctrough value determined at the end of the study. Linear regression methods tested for associations between CSF or CSF to plasma concentration ratio and covariates including pharmacokinetic parameters and CSF protein. Results: Ten patients (7 male; median [range] ± SD age 45.3 ± 2.8 y) completed the study. Median (intraquartile range [IQR]) lopinavir plasma 0- to 12-hour area under the curve (AUC0-12) and minimum concentrations were 71.3 h•μg/mL (48.4-87.6) and 3.82 /jg/mL (2.76-5.34). Median (IQR) CSF Ctrough, paired plasma concentration, and time since last dose were 11,200 pg/mL (6760–16.400), 5.42 μg/mL (3.88–5.85), and 9.9 hours (9.7-10.2), respectively. Median (IQR) CSF to plasma concentration ratio was 0.225% (0.194-0,324). Lopinavir CSF Ctrough was above the median 50% inhibitory concentration (IC50) for wild-type HIV-1 (wfHIV-1) (1900 pg/mL) in all subjects. Lopinavir plasma AUC0-12 (r2= 0.65; p = 0.009) and CSF protein (r2 = 0.26; p = 0.006) were associated with lopinavir CSF concentration, while CSF protein (r2 = 0.66; p = 0.008) was associated with CSF to plasma concentration ratio. Conclusions: Lopinavir CSF Ctrough was above the median IC50 for wfHIV-1 replication in all patients receiving lopinavir/ritonavir 400/100-mg soft-gel capsules twice daily. </jats:sec

Effects of Valproic Acid Coadministration on Plasma Efavirenz and Lopinavir Concentrations in Human Immunodeficiency Virus-Infected Adults

Valproic acid (VPA) has the potential to benefit patients suffering from human immunodeficiency virus (HIV)-associated cognitive impairment. The purpose of this study was to determine if VPA affects the plasma concentration of efavirenz (EFV) or lopinavir. HIV type 1 (HIV-1)-infected patients receiving EFV or lopinavir-ritonavir (LPV/r) had 9 or 10 blood samples drawn over 8 to 24 h of a dosing interval at steady state before and after receiving 250 mg of VPA twice daily for 7 days. VPA blood samples drawn before (C(0)) and 8 h after the morning dose (8 h) were compared to blood samples from a group of HIV-1-infected subjects who were taking either combined nucleoside reverse transcriptase inhibitors alone or had discontinued antiretroviral therapy. Pharmacokinetic parameters were calculated by noncompartmental analysis, and tests of bioequivalence were based on 90% confidence intervals (CIs) for ratios or differences. The geometric mean ratio (GMR) (90% CI) of the areas under the concentration-time curve from 0 to 24 h (AUC(0-24)s) of EFV (n = 11) with and without VPA was 1.00 (0.85, 1.17). The GMR (90% CI) of the AUC(0-8)s of LPV (n = 8) with and without VPA was 1.38 (0.98, 1.94). The differences (90% CI) in mean C(0) and 8-h VPA concentrations versus the control (n = 11) were −1.0 (−9.4, 7.4) μg/ml and −2.1 (−11.1, 6.9) μg/ml for EFV (n = 10) and −5.0 (−13.2, 3.3) μg/ml and −6.7 (−17.6, 4.2) μg/ml for LPV/r (n = 11), respectively. EFV administration alone is bioequivalent to EFV and VPA coadministration. LPV concentrations tended to be higher when the drug was combined with VPA. Results of VPA comparisons fail to raise concern that coadministration with EFV or LPV/r will significantly influence trough concentrations of VPA

Deliberate integration of student leadership development in doctor of pharmacy programs

The CAPE 2013 Outcomes answered the call for increased student leadership development (SLD) by identifying leadership as a desired curricular goal. To meet this outcome, colleges and schools of pharmacy are advised to first identify a set of SLD competencies aligned with their institution’s mission and goals and then organize these competencies into a SLD framework/model. Student leadership development should be integrated vertically and horizontally within the curriculum in a deliberate and longitudinal manner. It should include all student pharmacists, begin at the point of admission, and extend beyond extracurricular activities. The school’s assessment plan should be aligned with the identified SLD competencies so student learning related to leadership is assessed. To accomplish these recommendations, a positive environment for SLD should be cultivated within the school, including administrative backing and resources, as well as support among the broader faculty for integrating SLD into the curriculum

COVID-19 Roundtable

The past year was an unprecedentedly challenging period to humanity. The very concept of a pandemic indicates a profound impact across different regions and societal strata, rendering the idea of unscathed human lives almost unimaginable. Still, this image of COVID-19 as a global threat menacing us all must not be allowed to efface the specificity of individual or communal struggles. This caveat is particularly relevant in the context of gender and diversity studies – the pertinence of which has been underscored countlessly over the past months, especially in policy recommendations to the COVID-19 pandemic. From the disproportionately severe measures aggravating isolation and destitution among the elderly to the coalescence of sanitary regulations and the BLM protests or the fire in the Moria refugee camp and the resulting urgency to address the wellbeing of displaced people: issues that relate intimately to notions of marginalization continually surface adjacent to the health crisis proper. Whether explicitly or implicitly, these circumstances call for gender and diversity scholars to commit their expertise to the benefit of those inordinately affected by COVID-19 and the array of responses it has evoked worldwide. At the same time, the conditions affecting these groups and individuals also affect research activities and advocacy work on gender and diversity, inhibiting the active commitment and scholarly involvement the situation demands. In this Spring 2021 General Issue, the Journal of Diversity and Gender Studies (DiGeSt) sought to explore the paradoxes, contradictions and tensions scholars in our field have faced and continue to face during the current COVID-19 crisis. Transcending a formally academic register, the roundtable includes personal, situated accounts that engage tensions between the pandemic and scholarly work in diversity and gender studies

Effects of Minocycline and Valproic Acid Coadministration on Atazanavir Plasma Concentrations in Human Immunodeficiency Virus-Infected Adults Receiving Atazanavir-Ritonavir▿

Minocycline and valproic acid are potential adjuvant therapies for the treatment of human immunodeficiency virus (HIV)-associated cognitive impairment. The purpose of this study was to determine whether minocycline alone or in combination with valproic acid affected atazanavir plasma concentrations. Twelve adult HIV-infected subjects whose regimen included atazanavir (300 mg)-ritonavir (100 mg) daily for at least 4 weeks were enrolled. Each subject received atazanavir-ritonavir on day 1, atazanavir-ritonavir plus 100 mg minocycline twice daily on days 2 to 15, and atazanavir-ritonavir plus 100 mg minocycline twice daily and 250 mg valproic acid twice daily on days 16 to 30 with meals. The subjects had 11 plasma samples drawn over a dosing interval on days 1, 15, and 30. The coadministration of minocycline and valproic acid with atazanavir-ritonavir was well tolerated in all 12 subjects (six male; mean [± standard deviation] age was 43.1 [8.2] years). The geometric mean ratios (GMRs; 95% confidence interval [CI]) for the atazanavir area under the concentration-time curve from 0 to 24 h at steady state (AUC0-24), the plasma concentration 24 h after the dose (Cmin), and the maximum concentration during the dosing interval (Cmax) with and without minocycline were 0.67 (0.50 to 0.90), 0.50 (0.28 to 0.89), and 0.75 (0.58 to 0.95), respectively. Similar decreases in atazanavir exposure were seen after the addition of valproic acid. The GMRs (95% CI) for atazanavir AUC0-24, Cmin, and Cmax with and without minocycline plus valproic acid were 0.68 (0.43 to 1.06), 0.50 (0.24 to 1.06), and 0.66 (0.41 to 1.06), respectively. Coadministration of neither minocycline nor minocycline plus valproic acid appeared to influence the plasma concentrations of ritonavir (P > 0.2). Minocycline coadministration resulted in decreased atazanavir exposure, and there was no evidence that the addition of valproic acid mediated this effect

Pharmacokinetics of Indinavir and Nelfinavir in Treatment-Naive, Human Immunodeficiency Virus-Infected Subjects

AIDS Clinical Trials Group protocol 388 was designed to compare a three-drug regimen (indinavir with dual nucleosides) to a four-drug regimen (indinavir plus nelfinavir or indinavir plus efavirenz with dual nucleosides). Blood samples from patients taking indinavir and nelfinavir were collected over 8 to 12 h following a specified dose and were analyzed with high-performance liquid chromatography. Pharmacokinetic data were derived by using noncompartmental analysis. Following administration of indinavir every 8 h in the absence of nelfinavir (n = 8), the median predose indinavir concentration (C(0)) was 369 ng/ml (range, <10 to 949 ng/ml; one subject had a concentration of <10 ng/ml), and the concentration 8 h after administration of the study dose was 159 ng/ml (range, 85 to 506 ng/ml). In the group receiving 1,000 mg of indinavir every 12 h with nelfinavir (n = 10), the median indinavir C(0) was <10 ng/ml (range, <10 to 3,740 ng/ml; six subjects had a value of <10 ng/ml), and the C(12 h) was 44 ng/ml (range, <10 to 4,236 ng/ml; five subjects had a value of <10 ng/ml), while the subjects who received 1,200 mg of indinavir every 12 h with nelfinavir (n = 7) had a C(0) of 146 ng/ml (range, 58 to 5,215 ng/ml) and a C(12 h) of 95 ng/ml (range, 12 to 954 ng/ml). Indinavir clearance was significantly lower in the presence of nelfinavir (median [interquartile range], 34.1 liters/h [range, 22.6 to 45.8 liters/h] versus 47.9 liters/h [range, 42.7 to 70.3 liters/h]; P < 0.017). For subjects receiving 1,000 mg of indinavir every 12 h, the median C(0) value for nelfinavir (n = 9) was 1,779 ng/ml (range, <187.5 to 4,579 ng/ml), and the C(12 h) was 1,554 ng/ml (range, <187.5 to 5,540 ng/ml). Due to the unacceptable number of undetectable indinavir trough concentrations, 1,200 mg of indinavir appears to be the preferred dose in a twice-daily regimen that includes nelfinavir

Indinavir, Efavirenz, and Abacavir Pharmacokinetics in Human Immunodeficiency Virus-Infected Subjects

Adult AIDS Clinical Trials Group (AACTG) Protocol 886 examined the dispositions of indinavir, efavirenz, and abacavir in human immunodeficiency virus-infected subjects who received indinavir at 1,000 mg every 8 h (q8h) and efavirenz at 600 mg q24h or indinavir at 1,200 mg and efavirenz at 300 mg q12h with or without abacavir 300 at mg q12h. Thirty-six subjects participated. The median minimum concentration in plasma (C(min)) for indinavir administered at 1,200 mg q12h was 88.1 nM (interquartile range [IR], 61.7 to 116.5 nM), whereas the median C(min) for indinavir administered at 1,000 mg q8h was 139.3 nM (IR, 68.8 to 308.7 nM) (P = 0.19). Compared to the minimum C(min) range for wild-type virus (80 to 120 ng/ml) estimated by the AACTG Adult Pharmacology Committee, the C(min) for indinavir administered at 1,200 mg q12h (54 ng/ml) is inadequate. The apparent oral clearance (CL/F) (P = 0.28), apparent volume of distribution at steady state (V(ss)/F) (P = 0.25), and half-life (t(1/2)) (P = 0.80) of indinavir did not differ between regimens. The levels of efavirenz exposure were similar between regimens. For efavirenz administered at 600 mg q24h and 300 mg q12h, the median maximum concentrations in plasma (C(max)s) were 8,968 nM (IR, 5,784 to 11,768 nM) and 8,317 nM (6,587 to 10,239 nM), respectively (P = 0.66), and the C(min)s were 4,289 nM (IR, 2,462 to 5,904 nM) and 4,757 nM (IR, 3,088 to 6,644 nM), respectively (P = 0.29). Efavirenz pharmacokinetic parameters such as CL/F (P = 0.62), V(ss)/F (P = 0.33), and t(1/2) (P = 0.37) were similar regardless of the dosing regimen. The median C(max), C(min), CL/F, V(ss)/F, and t(1/2) for abacavir were 6,852 nM (IR, 5,702 to 7,532), 21.0 nM (IR, 21.0 to 87.5), 43.7 liters/h (IR, 37.9 to 55.2), 153.9 liters (IR, 79.6 to 164.4), and 2.0 h (IR, 1.8 to 2.8), respectively. In summary, when indinavir was given with efavirenz, the trough concentration of indinavir after administration of 1,200 mg q12h was inadequate. Abacavir did not influence the pharmacokinetics or exposure parameters of either indinavir or efavirenz. The levels of efavirenz exposure were similar in subjects receiving efavirenz q12h or q24h

COVID-19 Roundtable

DiGeSt 8(1) General Issue - COVID-19 Roundtable</jats:p