Moderate hepatic impairment increased exposure to letermovir <2-fold, while severe hepatic impairment increased letermovir exposure approximately 4-fold as compared with healthy subjects. Letermovir 60/30 mg/day was generally well-tolerated in subjects with hepatic impairment.
The pharmacokinetics and safety of the novel herpes simplex virus helicase‐primase inhibitor pritelivir were evaluated in 5 phase 1 trials: a single‐ascending‐dose trial, 2 multiple‐ascending‐dose trials, a food‐effect trial, and an absolute bioavailability trial in healthy male subjects. One cohort of healthy female subjects was included in the single‐ascending‐dose trial. Pritelivir pharmacokinetics were linear up to 480 mg following single and up to 400 mg following multiple once‐daily doses. The half‐life ranged from 52 to 83 hours, and steady state was reached between 8 and 13 days. Maximum plasma concentration and area under the plasma concentration–time curve from time 0 to the last quantifiable concentration were 1.5‐ and 1.1‐fold higher in female compared to male subjects. Absolute bioavailability was 72% under fasted conditions. Following a fatty diet, pritelivir time to maximum concentration was 1.5 hour delayed and maximum plasma concentration and area under the plasma concentration–time curve from time 0 to the last quantifiable concentration were 33% and 16% higher, respectively. Pritelivir was safe and well tolerated up to 600 mg following single and up to 200 mg following multiple once‐daily doses. Considering a therapeutic dose of 100 mg once‐daily, pritelivir demonstrated a favorable safety and tolerability and pharmacokinetic profile in healthy subjects to support further development.
Letermovir is a human cytomegalovirus (CMV) terminase inhibitor for the prophylaxis of CMV infection and disease in allogeneic hematopoietic stem-cell transplant recipients. In vitro studies have identified letermovir as a potential cytochrome P450 (CYP) 3A inhibitor. Thus, the effect of letermovir on the CYP3A isoenzyme-specific probe drug midazolam was investigated in a phase 1 trial. Healthy female subjects received single-dose intravenous (IV; 1 mg) and oral (2 mg) midazolam on days -4 and -2, respectively. Letermovir 240 mg once daily was administered on days 1 to 6, and further single doses of midazolam 1 mg IV and oral midazolam 2 mg were administered on days 4 and 6, respectively. Pharmacokinetics, tolerability, and safety were monitored throughout the trial. Following coadministration with letermovir, the least square means ratio for maximum plasma concentration and area under the plasma concentrationtime curve from time 0 to the last measurable concentration was 172.4% and 225.3%, respectively, for oral midazolam, and 105.2% and 146.6%, respectively, for midazolam IV. The area under the plasma concentration-time curve from time 0 to the last measurable concentration ratio of midazolam to 1-hydroxymidazolam increased slightly in the presence of letermovir following IV (8.8-13.1; 49% increase) and oral (3.3-5.3; 59% increase) midazolam. Letermovir reached steady state, on average, by days 5 to 6. All treatments were generally well tolerated. Letermovir demonstrated moderate CYP3A inhibition.
We report the case of a girl who has joint and skin laxity with atrophic scarring, and was diagnosed at birth with a Dandy-Walker malformation. She subsequently developed joint contractures, hydrocephalus and syringomyelia. This case shows some similarities to Ehlers-Danlos syndrome type VI, but with no evidence of lysyl hydroxylase deficiency or ocular fragility. It is likely that she represents a distinct and recognizable syndrome. There was parental consanguinity and a subsequent pregnancy resulted in a similarly affected fetus, suggesting autosomal recessive inheritance.
Introduction Antisynthetase syndrome (ASS) is a rare idiopathic inflammatory myopathy with nearly 89% showing interstitial lung disease (ILD). The hallmark of ASS is the presence of serum autoantibodies directed against aminoacyl-tRNA synthetases that include Jo-1 (most commonly detected), PL-7, PL-12, OJ, EJ, KS, Wa, YRS and Zo. However, in a small subpopulation without evidence of myositis, the diagnosis may be critically delayed, hindering management of this rapidly progressive disease. We report an interesting case of anti-PL-12/anti-SSA 52kD ASS presenting as acute digital ischemia, an association rarely described previously. In cases with ILD, the severity of lung condition generally determines the prognosis. Case description A 77-year-old Caucasian female presented with sudden onset of painful, blue discolouration in her bilateral fingertips two-weeks after mild lower respiratory tract infection and occasional pyrexia. She was a non-smoker, otherwise independent lady who had background history of ischemic heart disease, diverticulosis and hypertension. Her physical examination revealed dusky blue digits and dry ulceration. She had extensive investigations that showed raised CRP (61mg/L), eGFR 39ml/min/1.73m2 , weak positive rheumatoid factor and cold agglutinins, equivocal Lupus anticoagulant, negative ANCA, clear urinalysis, bilateral chronic inflammatory change on chest xray and thrombi of digital arteries on Doppler ultrasound of hands. She was initially treated for infection due to ongoing temperatures and had multiple scans with no definite source. An inflammatory aetiology was then thought likely due to lack of response to antibiotics and steroid therapy was commenced with settling of fevers and inflammatory markers. Autoimmune screens initially were negative but became more prominent over time with a positive Ro antibody and ultimately a positive Anti PL12 antibody, keeping with anti-synthetase syndrome. She subsequently developed florid interstitial lung disease, further ischemia and ultimately necrosis of her fingertips. Due to the onset of lung disease she was treated with IV steroids, Cyclophosphamide and Prostaglandins with some initial benefit. She received 3 cycles of cyclophosphamide and managed to come off supplemental oxygen. However, she had issues with recurrent chest infections due to immunosuppressive therapy which resulted in delays in her cyclophosphamide pulses and need for antibiotics. She later developed clostridium-difficile gastroenteritis and subsequent ileus of her bowel which was managed conservatively and found it difficult to overcome. As time went on, the progress that she had made with her hands started to deteriorate again. There were also further issues with intestinal obstruction, and sadly ultimately passed away with aspiration pneumonia. Discussion ASS is recognized as a rare autoimmune inflammatory myopathy of unknown etiology, 2–3 times more prevalent in women than in men. The clinical manifestations include myositis, polyarthritis, ILD, mechanic’s hands, and Raynaud phenomenon. The hallmark of ASS is the presence of serum autoantibodies directed against aminoacyl-tRNA synthetases that include Jo-1, PL-7, PL-12, OJ, EJ, KS, Wa, YRS and Zo. Anti-jo1 is the most commonly detected antibody. These autoantibodies may arise after viral infections, or patients may have a genetic predisposition. Our case was interesting as the autoimmune profile was positive for Anti-Ro/SSA and anti-PL-12. Anti-Ro/SSA and anti-La/SSB are traditionally associated with Sjögren’s disease and Sjögren’s-related ILD, however, anti-Ro/SSA has been independently associated with ASS and more severe and fibrotic ILD. It has been described that patients with anti-PL-12-ASS are most often clinically diagnosed with amyopathic dermatomyositis or ILD alone and there is higher prevalence and increased severity of ILD than PM/DM. Moreover, the prevalence of muscle symptoms (weakness and myalgia) is significantly lower in patients with anti-PL7/PL12 as compared to those with anti-Jo1 and less associated with malignancy as compared to DM. Interestingly, anti-PL-12 is also associated with higher rates of Raynaud phenomenon. Our case also reports that not all patients with antisynthetase antibodies or even those classified as ASS have all manifestations of this syndrome. Diagnostic criteria refers to presence of antisynthetase antibody plus two major criteria or one major criterion and two minor criteria (Solomon et all. 2011) or one or more of clinical features (Connors et all.2010). When the lungs are affected, the severity and extent of lung damage generally determines the prognosis because respiratory failure is the leading cause of death. Clinical presentation guides towards therapeutic management that mostly includes corticosteroids, immunosuppressive medications, and/or physical therapy Key learning points Digital ischemia could be a rare presentation of ASS. Clinical features of antisynthetase syndrome (ASS) include interstitial lung disease, ‘mechanic’ hands, myositis, polyarthritis and Raynaud’s phenomenon. Extensive myositis specific antibody testing is strongly recommended even if screening autoimmune serologies are unrevealing. Anti- PL-12 ASS has significantly lower prevalence of muscle symptoms (weakness and myalgia) and more association with Raynaud’s phenomenon as compared to those with anti-Jo1. It is imperative to recognize lesser-known manifestations of ASS in the absence of clinical myositis as delay in diagnosis and treatment worsens the prognosis. Conflicts of interest The authors have declared no conflicts of interest.
Letermovir is a human cytomegalovirus (CMV) terminase inhibitor approved in the United States, Canada, Japan, and the European Union for prophylaxis of CMV infection and disease in CMV-seropositive, allogeneic, hematopoietic stem-cell transplant recipients. In vitro, letermovir is a substrate and potential modulator of P-glycoprotein. The potential of letermovir to alter the pharmacokinetics of digoxin (a P-glycoprotein substrate) upon coadministration in healthy subjects was therefore investigated in a phase 1 trial (EudraCT: 2011-004516-39). Oral letermovir 240 mg was administered twice daily for 12 days with a single oral digoxin 0.5-mg dose on day 7; after a washout period, oral digoxin 0.5 mg was administered on day 35 (sequence 1). The period order was reversed after a 28-day washout for sequence 2. Pharmacokinetics and safety were evaluated. The presence of steady-state letermovir reduced digoxin area under the plasma concentration-time curve from administration until last quantifiable measurement by 12% and maximum plasma concentration by 22% compared with digoxin alone; digoxin half-life and elimination rate remained similar in both conditions. The between-subject variability of digoxin maximum plasma concentration was higher with letermovir than without (42% vs 31%) and similar for digoxin area under the plasma concentration-time curve in both periods. No specific safety or tolerability concerns were identified. Overall, letermovir had no clinically relevant effect on concomitant administration with digoxin.
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