Kristina M. Brooks

Antiretroviral Boosting Agent Cobicistat Increases the Pharmacokinetic Exposure and Anticoagulant Effect of Dabigatran in HIV-Negative Healthy Volunteers

Drug interactions between antiretroviral therapy and anticoagulant medications are of particular concern given that ≈50% of the current HIV population is >50 years of age. Moreover, HIV infection is characterized by a hypercoaguable state and premature immunologic aging, in which thromboembolic events may be as much as 10 times more prevalent than in the general population across all age spectra.1 Dabigatran was the first direct oral anticoagulant approved by the US Food & Drug Administration and is the only direct oral anticoagulant with a US Food & Drug Administration -approved specific reversal agent, idarucizumab. Unlike warfarin and many other direct oral anticoagulants, dabigatran is not a substrate, inhibitor, or inducer of cytochrome P450 metabolic enzymes. However, dabigatran is a substrate of Permeability-glycoprotein (P-gp) and renal multidrug and toxin extrusion-1 transporters. Cobicistat is a US Food & Drug Administration -approved antiretroviral-boosting agent that is coformulated with numerous fixed-dose combination antiretroviral products because of its inhibitory effects on cytochrome P450 3A4. Currently, ≈40% of all treatment-naive patients with HIV in the United States are initiated on a cobicistat-boosted antiretroviral regimen. In addition to cytochrome P450 3A4, cobicistat is also an inhibitor of both P-gp and multidrug and toxin extrusion-1 transporters.2 Thus, this study aimed to determine whether the …

Pharmacokinetics, Pharmacodynamics, and Proposed Dosing of the Oral JAK1 and JAK2 Inhibitor Baricitinib in Pediatric and Young Adult CANDLE and SAVI Patients

Population pharmacokinetic (popPK) modeling was used to characterize the PK profile of the oral Janus kinase (JAK)1/JAK2 inhibitor, baricitinib, in 18 patients with Mendelian interferonopathies who are enrolled in a compassionate use program. Patients received doses between 0.1 to 17 mg per day. Covariates of weight and renal function significantly influenced volume‐of‐distribution and clearance, respectively. The half‐life of baricitinib in patients less than 40 kg was substantially shorter than in adult populations, requiring the need for dosing up to 4 times daily. On therapeutic doses, the mean area‐under‐the‐concentration‐vs.‐time curve was 2,388 nM*hr, which is 1.83‐fold higher than mean baricitinib exposures in adult patients with rheumatoid arthritis receiving doses of 4 mg once‐daily. Dose‐dependent decreases in interferon (IFN) biomarkers confirmed an in vivo effect of baricitinib on type‐1 IFN signaling. PopPK and pharmacodynamic data support a proposal for a weight‐ and estimated glomerular filtration rate‐based dosing regimen in guiding baricitinib dosing in patients with rare interferonopathies.

Cytokine-Mediated Systemic Adverse Drug Reactions in a Drug–Drug Interaction Study of Dolutegravir With Once-Weekly Isoniazid and Rifapentine

Background Once-weekly isoniazid and rifapentine for 3 months is a treatment option in persons with human immunodeficiency virus and latent tuberculosis infection. This study aimed to examine pharmacokinetic drug-drug interactions between this regimen and dolutegravir, a first-line antiretroviral medication. Methods This was a single-center, open-label, fixed-sequence, drug-drug interaction study in healthy volunteers. Subjects received oral dolutegravir 50 mg once daily alone (days 1-4) and concomitantly with once-weekly isoniazid 900 mg, rifapentine 900 mg, and pyridoxine 50 mg (days 5-19). Dolutegravir concentrations were measured on days 4, 14, and 19, and rifapentine, 25-desacetyl-rifapentine, and isoniazid concentrations were measured on day 19. Cytokines and antidrug antibodies to isoniazid and rifapentine were examined at select time points. Results The study was terminated following the development of flu-like syndrome and elevated aminotransferase levels in 2 of 4 subjects after the third isoniazid-rifapentine dose. Markedly elevated levels of interferon-γ, CXCL10, C-reactive protein, and other cytokines were temporally associated with symptoms. Antidrug antibodies were infrequently detected. Dolutegravir area under the curve (AUC) was decreased by 46% (90% confidence interval, 27-110%; P = .13) on day 14. Rifapentine and 25-desacetyl rifapentine levels on day 19 were comparable to reference data, whereas isoniazid AUCs were approximately 67%-92% higher in the subjects who developed toxicities. Conclusions The combined use of dolutegravir with once-weekly isoniazid-rifapentine resulted in unexpected and serious toxicities that were mediated by endogenous cytokine release. Additional investigations are necessary to examine the safety and efficacy of coadministering these medications. Clinical Trials Registration NCT02771249.

Alterations in Hydrocortisone Pharmacokinetics in a Patient With Congenital Adrenal Hyperplasia Following Bariatric Surgery

Management of adult patients with classic congenital adrenal hyperplasia (CAH) is challenging and often complicated by obesity, metabolic syndrome, and adverse cardiovascular risk. Alterations in weight can influence cortisol kinetics. A 19-year-old woman with classic CAH and morbid obesity experienced persistent elevations of androgen levels while receiving oral glucocorticoid therapy. Control of adrenal androgens was improved with continuous subcutaneous hydrocortisone infusion therapy, but obesity-related comorbidities persisted. After undergoing sleeve gastrectomy, the patient experienced dramatic weight loss, with improvement in insulin sensitivity and fatty liver in the postbariatric period. Cortisol clearance studies performed to evaluate changes in hydrocortisone dose requirements showed marked alternations in cortisol pharmacokinetics with decreases in volume of distribution and cortisol clearance, along with an increase in area under the curve for cortisol. Hydrocortisone dose was subsequently decreased 34% by 15 months after surgery. Effective control of androgen excess on this lower hydrocortisone dose was achieved and continues 27 months after surgery. This case highlights obesity-related complications of glucocorticoid replacement therapy in the management of CAH. Individual patient factors, such as fatty liver disease and insulin resistance, can have a clinically important effect on cortisol metabolism. Bariatric surgery was a safe and effective treatment of obesity in this patient with CAH and should be considered for patients with CAH and multiple obesity-related comorbidities.

Differential Influence of the Antiretroviral Pharmacokinetic Enhancers Ritonavir and Cobicistat on Intestinal P-Glycoprotein Transport and the Pharmacokinetic/Pharmacodynamic Disposition of Dabigatran

ABSTRACT Dabigatran etexilate (DE) is a P-glycoprotein (P-gp) probe substrate, and its active anticoagulant moiety, dabigatran, is a substrate of the multidrug and toxin extrusion protein-1 (MATE-1) transporter. The antiretroviral pharmacokinetic enhancers, ritonavir and cobicistat, inhibit both these transporters. Healthy volunteers received single doses of DE at 150 mg alone, followed by ritonavir at 100 mg or cobicistat at 150 mg daily for 2 weeks. DE was then given 2 h before ritonavir or cobicistat. One week later, DE was given simultaneously with ritonavir or cobicistat. No significant increases in dabigatran pharmacokinetic (PK) exposure or thrombin time (TT) measures were observed with the simultaneous administration of ritonavir. Separated administration of ritonavir resulted in a mean decrease in dabigatran PK exposure of 29% (90% confidence interval [CI], 18 to 40%) but did not significantly change TT measures. However, cobicistat increased dabigatran PK exposure (area under the concentration-versus-time curve from time zero to infinity and maximum plasma concentration) by 127% each (90% CI, 81 to 173% and 59 to 196%, respectively) and increased TT measures (33% for the area-under-the-effect curve from time zero to 24 h [90% CI, 22 to 44%] and 51% for TT at 24 h [90% CI, 22 to 78%]) when given simultaneously with dabigatran. Similar increases were observed when cobicistat was administered separately by 2 h from the administration of dabigatran. In all comparisons, no significant increase in the dabigatran elimination half-life was observed. Therefore, it is likely safe to coadminister ritonavir with DE, while there is a potential need for reduced dosing and prudent clinical monitoring with the coadministration of cobicistat due to the greater net inhibition of intestinal P-gp transport and increased bioavailability. (This study has been registered at ClinicalTrials.gov under identifier NCT01896622.)

Decreased Absorption of Dolutegravir and Tenofovir Disoproxil Fumarate, But Not Emtricitabine, in an HIV-Infected Patient Following Oral and Jejunostomy-Tube Administration

The use of enteral feeding tubes to administer antiretroviral medications is necessary in certain patients with human immunodeficiency virus (HIV) infection. However, adequacy of drug exposures after these administration routes are largely unknown, making dosing recommendations and the attainment of viral suppression challenging in this patient population. This report describes a patient with advanced HIV infection and a complicated medical history including long‐term intractable nausea/vomiting necessitating antiretroviral medication administration via a Roux‐en‐Y jejunostomy (J)‐tube. Pharmacokinetic assessments were performed to compare differences in antiretroviral drug absorption and plasma exposure following oral and J‐tube administration of dolutegravir, tenofovir disoproxil fumarate, and emtricitabine. Results were also compared with published pharmacokinetic data in HIV‐infected individuals. Exposure to dolutegravir and tenofovir were similar between J‐tube and oral administration routes, whereas emtricitabine exposure was 38% lower when administered via J‐tube. However, in comparison with reference data in HIV‐infected individuals taking these medications orally, exposure to dolutegravir and tenofovir was 75–76% and 55–61% lower, respectively, following both routes of administration. Emtricitabine exposure was similar to and 71% higher than reference data following J‐tube and oral administration, respectively. This report highlights the importance of performing pharmacokinetic assessments in patients with the potential for impaired drug absorption to ensure antiretroviral treatment success.

Drug interactions in HIV treatment: complementary & alternative medicines and over-the-counter products

ABSTRACT Introduction: Use of complementary and alternative medicines (CAMs) and over-the-counter (OTC) medications are very common among HIV-infected patients. These products can cause clinically significant drug-drug interactions (DDIs) with antiretroviral (ARV) medications, thereby increasing risk for negative outcomes such as toxicity or loss of virologic control. Areas covered: This article provides an updated review of the different mechanisms by which CAM and OTC products are implicated in DDIs with ARV medications. Expert commentary: Much of the literature published to date involves studies of CAMs interacting with older ARV agents via the cytochrome P450 (CYP450) system. However, the HIV treatment and prevention arsenal is continually evolving. Furthermore, our elucidation of the role of non-CYP450 mediated DDIs with ARV medications is greatly increasing. Therefore, clinicians are well served to understand the various mechanisms and extent by which new ARV therapies may be involved in drug interactions with CAMs and OTC medications.

Test Dose Pharmacokinetics in Pediatric Patients Receiving Once‐Daily IV Busulfan Conditioning for Hematopoietic Stem Cell Transplant: A Reliable Approach?

Intravenous (IV) busulfan test dose pharmacokinetics (PK) has been shown to accurately predict once‐daily dose requirements and improve outcomes in adult transplant patients, but there are limited data to support this approach in children. Test doses of busulfan ∼0.8 mg/kg were infused over 2 to 3 hours, followed by serial sampling to 4‐6 hours postinfusion in pediatric hematopoietic stem cell transplant recipients (n = 5). Once‐daily busulfan doses were calculated based on a myelosuppressive area under the concentration‐time curve (AUC) target of ∼3700 to 4000 μmol·min/L and assumed dose‐proportionality to the test dose. PK analysis was then repeated at full daily doses within 6‐8 days of test dose administration. Plasma PK samples collected under test and full‐dose conditions were analyzed using validated commercial assays and noncompartmental methods. In 4 out of 5 patients, PK estimates after once‐daily IV busulfan administration differed in comparison to test dose estimates (AUC range –38.2% to +49.7%, clearance range –34.3% to +61.8%). Patients 1, 2, and 3 required increases in remaining daily busulfan doses to achieve AUC targets, and no adjustment was required in patient 4. Patient 5s AUC was 49.7% higher than expected, and he subsequently developed fatal sinusoidal obstruction syndrome. In our experience with pediatric patients, test dose PK failed to reliably predict daily dosing requirements with large discrepancies from predicted AUC targets. This article highlights the necessity for therapeutic drug monitoring of IV busulfan and inadvisability of relying solely on test‐dose busulfan PK in pediatric patients. Furthermore, clinicians should consider strategies to expedite dose adjustments in real time.