Myrcludex B acts as a hepatitis B and D virus entry inhibitor blocking the sodium taurocholate cotransporting polypeptide (SLC10A1). We investigated the effects of myrcludex B on plasma bile acid ...disposition, tenofovir pharmacokinetics, and perpetrator characteristics on cytochrome P450 (CYP) 3A. Twelve healthy volunteers received 300 mg tenofovir disoproxil fumarate orally and 10 mg subcutaneous myrcludex B. Myrcludex B increased total plasma bile acid exposure 19.2‐fold without signs of cholestasis. The rise in conjugated bile acids was up to 124‐fold (taurocholic acid). Coadministration of tenofovir with myrcludex B revealed no relevant changes in tenofovir pharmacokinetics. CYP3A activity slightly but significantly decreased by 29% during combination therapy. Myrcludex B caused an asymptomatic but distinct rise in plasma bile acid concentrations and had no relevant impact on tenofovir pharmacokinetics. Changes in CYP3A activity might be due to alterations in bile acid signaling. Long‐term effects of elevated bile acids will require critical evaluation.
The objective of the study was to establish an in vivo method for assessing cytochrome P450 3A (CYP3A) activity using therapeutically inert nanogram doses of midazolam. We administered four ...escalating single doses of oral midazolam (0.0001–3 mg) to 12 healthy participants, stratified according to CYP3A5 carrier status, to assess pharmacokinetics linearity. We then evaluated the interactions with the CYP3A inhibitor ketoconazole (400 mg q.d.) after nanogram and regular doses of midazolam. Area under the plasma concentration–time curve (AUC) and peak plasma concentration (Cmax) were linear over the entire range of doses. Ketoconazole reduced midazolam oral clearance by 92.8%. AUC and Cmax increased by 1,540 and 363%, respectively. CYP3A5 carrier status had no influence on midazolam oral clearance or its inhibition by ketoconazole. This is the first study showing that midazolam pharmacokinetics is linear in a 30,000–fold concentration range, and therefore that nano– and microgram doses of midazolam can reliably predict the pharmacokinetics of midazolam in therapeutic doses and can be used to assess CYP3A activity even in the presence of strong CYP3A inhibitors.
Clinical Pharmacology & Therapeutics (2013); 93 6, 564–571. doi:10.1038/clpt.2013.27
The objective of this study was to assess the incidence, timing and identify pharmacogenetic, efavirenz (EFV) pharmacokinetic and biochemical predictors of EFV-based antiretroviral therapy (ART) ...drug-induced liver injury (DILI). ART-naïve HIV patients (n = 285) were prospectively enrolled. Pretreatment laboratory evaluations included hepatitis B surface antigen and C antibody, CD4 count and viral load. Liver tests were done at baseline, 1st, 2nd, 4th, 8th, 12th, 24th and 48th weeks during ART. Plasma EFV and 8-hydroxyefvairenz concentration was determined at week 4 using liquid chromatography-mass spectrometry. CYP2B6, CYP3A5, ABCB1 3435C/T and UGT2B7*2 genotyping was done using Taqman genotyping assay. Data were analyzed using survival analysis and Cox proportional hazards model. The incidence of DILI was 15.7% or 27.9 per 100 person-years and that of severe injury was 3.4% or 6.13 per 100 person-years. The median time for the development of DILI and severe injury was 2 and 4 weeks after initiation of ART, respectively. There was significant association of DILI with lower baseline platelet, albumin, log plasma viral load and CD4 count (P = 0.031, 0.037, 0.06 and 0.019, respectively). Elevated baseline alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, plasma EFV level and CYP2B6*6 were good predictors for the development of DILI (P = 0.03, 0.01, 0.016, 0.017 and 0.04, respectively). We report for the first time CYP2B6*6 as a putative genetic marker and high plasma EFV concentration as intermediate biomarker for vulnerability to EFV-induced liver injury in HIV patients. CYP2B6 genotyping and/or regular monitoring of EFV and lever enzymes level during early therapy is advised for early diagnosis and management of DILI.
We established a new limited sampling strategy to assess CYP3A activity and evaluated the time course of reversible (voriconazole) and irreversible (ritonavir) CYP3A inhibition. In this randomized ...trial, two groups, each with eight healthy participants, received CYP3A inhibitors voriconazole or ritonavir orally for 9 days, with 3 mg midazolam (MDZ) administered before the inhibitor treatment, on days 1, 2, 3, 5, 8, and 9 during inhibitor treatment, and on days 10, 11, and 12 (3 days) after discontinuation. Plasma MDZ area under the curve (AUC) between 2 and 4 h after oral administration in the form of a solution strongly correlated with MDZ clearance. Using this parameter, maximum inhibition of voriconazole and ritonavir was calculated to have occurred only 48 h after starting of the inhibitor (percentage of baseline MDZ clearance, voriconazole: 10.6%; ritonavir: 8.4%). Recovery of CYP3A activity occurred with a half‐life of 24 h after voriconazole, whereas ritonavir inhibition was still strong 3 days after discontinuation. These findings underscore the substantial and gradual alterations in dose requirements in the first days of and after such combination therapies.
Clinical Pharmacology & Therapeutics (2011); 90 5, 666–673. doi:10.1038/clpt.2011.164
Acute markers of spinal cord injury are essential for both diagnostic and prognostic purposes. The goal of this study was to assess the relationship between early MR imaging biomarkers after acute ...cervical spinal cord injury and to evaluate their predictive validity of neurologic impairment.
We performed a retrospective cohort study of 95 patients with acute spinal cord injury and preoperative MR imaging within 24 hours of injury. The American Spinal Injury Association Impairment Scale was used as our primary outcome measure to define neurologic impairment. We assessed several MR imaging features of injury, including axial grade (Brain and Spinal Injury Center score), sagittal grade, length of injury, maximum canal compromise, and maximum spinal cord compression. Data-driven nonlinear principal component analysis was followed by correlation and optimal-scaled multiple variable regression to predict neurologic impairment.
Nonlinear principal component analysis identified 2 clusters of MR imaging variables related to 1) measures of intrinsic cord signal abnormality and 2) measures of extrinsic cord compression. Neurologic impairment was best accounted for by MR imaging measures of intrinsic cord signal abnormality, with axial grade representing the most accurate predictor of short-term impairment, even when correcting for surgical decompression and degree of cord compression.
This study demonstrates the utility of applying nonlinear principal component analysis for defining the relationship between MR imaging biomarkers in a complex clinical syndrome of cervical spinal cord injury. Of the assessed imaging biomarkers, the intrinsic measures of cord signal abnormality were most predictive of neurologic impairment in acute spinal cord injury, highlighting the value of axial T2 MR imaging.
Objectives
Constituents of St John's wort (SJW) in vivo induce the cytochrome P450 (CYP) isozymes 3A4, 2C9, and 2C19 but in vitro were shown to inhibit them. This study investigates both short‐ and ...long‐term effects of SJW on the antifungal voriconazole, which is metabolized by these enzymes.
Methods
In a controlled, open‐label study, single oral doses of 400 mg voriconazole were administered to 16 healthy men stratified for CYP2C19 genotype before and on day 1 and day 15 of concomitant SJW intake (300 mg LI 160 3 times daily). Plasma and urine concentrations of voriconazole were determined by liquid chromatography with mass‐spectrometric detection.
Results
During the initial 10 hours of the first day of SJW administration, the area under the voriconazole plasma concentration–time curve was increased by 22% compared with control (15.5 ± 6.84 h · μg/mL versus 12.7 ± 4.16 h · μg/mL, P = .02). After 15 days of SJW intake, the area under the plasma concentration–time curve from hour 0 to infinity was reduced by 59% compared with control (9.63 ± 6.03 h · μg/mL versus 23.5 ± 15.6 h · μg/mL, P = .0004), with a corresponding increase in oral voriconazole clearance (CL/F) from 390 ± 192 to 952 ± 524 mL/min (P = .0004). The baseline CL/F of voriconazole and the absolute increase in CL/F were smaller in carriers of 1 or 2 deficient CYP2C19*2 alleles compared with wild‐type individuals (P < .03).
Conclusions
Coadministration of SJW leads to a short‐term but clinically irrelevant increase followed by a prolonged extensive reduction in voriconazole exposure. SJW might put CYP2C19 wild‐type individuals at highest risk for potential voriconazole treatment failure.
Clinical Pharmacology & Therapeutics (2005) 78, 25–33; doi: 10.1016/j.clpt.2005.01.024
Highlights • About 80% of drug interaction alerts are potentially sensitive to context factors. • Promising context factors refer to comedication, potassium and renal function. • Context factors ...should urgently be implemented in drug interaction alerting systems.
Objectives
Cytochrome P450 (CYP) 2C19 and CYP3A4 are the major enzymes responsible for voriconazole elimination. Because the activity of CYP2C19 is under genetic control, the extent of inhibition ...with a CYP3A4 inhibitor was expected to be modulated by the CYP2C19 metabolizer status. This study thus assessed the effect of the potent CYP3A4 inhibitor ritonavir after short‐term administration on voriconazole pharmacokinetics in extensive metabolizers (EMs) and poor metabolizers (PMs) of CYP2C19.
Methods
In a randomized, placebo‐controlled crossover study, 20 healthy participants who were stratified according to CYP2C19 genotype received oral ritonavir (300 mg twice daily) or placebo for 2 days. Together with the first ritonavir or placebo dose, a single oral dose of 400 mg voriconazole was administered. Voriconazole was determined in plasma and urine by liquid chromatography‐mass spectrometry, and pharmacokinetic parameters were estimated by noncompartmental analysis.
Results
When given alone, the apparent oral clearance of voriconazole after single oral dosing was 26% ± 16% (P > .05) lower in CYP2C19*1/*2 individuals and 66% ± 14% (P < .01) lower in CYP2C19 PMs. The addition of ritonavir caused a major reduction in voriconazole apparent oral clearance (354 ± 173 mL/min versus 202 ± 139 mL/min, P = .0001). This reduction occurred in all CYP2C19 genotypes (463 ± 168 mL/min versus 305 ± 112 mL/min P = .023 for *1/*1, 343 ± 127 mL/min versus 190 ± 93 mL/min P = .008 for *1/*2, and 158 ± 54 mL/min versus 22 ± 11 mL/min for *2/*2) and is probably caused by inhibition of CYP3A4‐mediated voriconazole metabolism.
Conclusions
Coadministration of a potent CYP3A4 inhibitor leads to a higher and prolonged exposure with voriconazole that might increase the risk of the development of adverse drug reactions on a short‐term basis, particularly in CYP2C19 PM patients.
Clinical Pharmacology & Therapeutics (2006) 80, 126–135; doi: 10.1016/j.clpt.2006.04.004
Predicting neurological recovery after spinal cord injury (SCI) is challenging. Using topological data analysis, we have previously shown that mean arterial pressure (MAP) during SCI surgery predicts ...long-term functional recovery in rodent models, motivating the present multicenter study in patients.
Intra-operative monitoring records and neurological outcome data were extracted (n = 118 patients). We built a similarity network of patients from a low-dimensional space embedded using a non-linear algorithm, Isomap, and ensured topological extraction using persistent homology metrics. Confirmatory analysis was conducted through regression methods.
Network analysis suggested that time outside of an optimum MAP range (hypotension or hypertension) during surgery was associated with lower likelihood of neurological recovery at hospital discharge. Logistic and LASSO (least absolute shrinkage and selection operator) regression confirmed these findings, revealing an optimal MAP range of 76-104-117 mmHg associated with neurological recovery.
We show that deviation from this optimal MAP range during SCI surgery predicts lower probability of neurological recovery and suggest new targets for therapeutic intervention.
NIH/NINDS: R01NS088475 (ARF); R01NS122888 (ARF); UH3NS106899 (ARF); Department of Veterans Affairs: 1I01RX002245 (ARF), I01RX002787 (ARF); Wings for Life Foundation (ATE, ARF); Craig H. Neilsen Foundation (ARF); and DOD: SC150198 (MSB); SC190233 (MSB).
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