The British Journal of Clinical Pharmacology: The first 50 years.

The British Journal of Clinical Pharmacology celebrates its 50th anniversary of publication in 2023. Here four previous Editors-in-Chief and the current Editor reflect on the Journal's history and the changes that have occurred during that time.

Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component.

BACKGROUND: The amyloid fibril deposits that cause systemic amyloidosis always contain the nonfibrillar normal plasma protein, serum amyloid P component (SAP). The drug (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC) efficiently depletes SAP from the plasma but leaves some SAP in amyloid deposits that can be specifically targeted by therapeutic IgG anti-SAP antibodies. In murine amyloid A type amyloidosis, the binding of these antibodies to the residual SAP in amyloid deposits activates complement and triggers the rapid clearance of amyloid by macrophage-derived multinucleated giant cells. METHODS: We conducted an open-label, single-dose-escalation, phase 1 trial involving 15 patients with systemic amyloidosis. After first using CPHPC to deplete circulating SAP, we infused a fully humanized monoclonal IgG1 anti-SAP antibody. Patients with clinical evidence of cardiac involvement were not included for safety reasons. Organ function, inflammatory markers, and amyloid load were monitored. RESULTS: There were no serious adverse events. Infusion reactions occurred in some of the initial recipients of larger doses of antibody; reactions were reduced by slowing the infusion rate for later patients. At 6 weeks, patients who had received a sufficient dose of antibody in relation to their amyloid load had decreased liver stiffness, as measured with the use of transient elastography. These patients also had improvements in liver function in association with a substantial reduction in hepatic amyloid load, as shown by means of SAP scintigraphy and measurement of extracellular volume by magnetic resonance imaging. A reduction in kidney amyloid load and shrinkage of an amyloid-laden lymph node were also observed. CONCLUSIONS: Treatment with CPHPC followed by an anti-SAP antibody safely triggered clearance of amyloid deposits from the liver and some other tissues. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01777243.).

Lack of effect of oral cabotegravir on the pharmacokinetics of a levonorgestrel/ethinyl oestradiol-containing oral contraceptive in healthy adult women.

AIMS: This study aimed to investigate whether cabotegravir (CAB), an integrase inhibitor in development for treatment and prevention of human immunodeficiency virus-1, influences the pharmacokinetics (PK) of a levonorgestrel (LNG) and ethinyl oestradiol (EO)-containing oral contraceptive (OC) in healthy women. METHODS: In this open-label, fixed-sequence crossover study, healthy female subjects received LNG 0.15 mg/EO 0.03 mg tablet once daily Days 1-10 alone and with oral CAB 30 mg once daily Days 11-21. At the end of each treatment period, subjects underwent predose sampling for concentrations of follicle-stimulating hormone, luteinizing hormone, and progesterone and serial PK sampling for plasma LNG, EO, and CAB concentrations. RESULTS: Twenty women were enrolled, and 19 completed the study. One subject was withdrawn due to an adverse event unrelated to study medications. Geometric least squares mean ratios (90% confidence interval) of LNG + CAB vs. LNG alone for LNG area under the plasma concentration-time curve over the dosing interval of duration τ and maximum observed plasma concentration were 1.12 (1.07-1.18) and 1.05 (0.96-1.15), respectively. Geometric least squares mean ratio (90% confidence interval) of EO + CAB vs. EO alone for EO area under the plasma concentration-time curve over the dosing interval of duration τ and maximum observed plasma concentration were 1.02 (0.97-1.08) and 0.92 (0.83-1.03), respectively. Steady-state CAB PK parameters were comparable to historical values. There was no apparent difference in mean luteinizing hormone, follicle-stimulating hormone, and progesterone concentrations between periods. No clinically significant trends in laboratory values, vital signs, or electrocardiography values were observed. CONCLUSIONS: Repeat doses of oral CAB had no significant effect on LNG/EO PK or pharmacodynamics, which supports CAB coadministration with LNG/EO OCs in clinical practice.

Endothelial function and arterial compliance are not impaired in subjects with heart failure of non-ischemic origin.

BACKGROUND: Patients with heart failure and underlying ischemic heart disease (IHD) exhibit both endothelial dysfunction and increased arterial stiffness. We investigated whether this is also the case in heart failure of nonischemic etiology. METHODS AND RESULTS: Eleven patients with heart failure and IHD, 12 patients with heart failure from angiographically verified idiopathic nonischemic dilated cardiomyopathy (DCM), and 16 healthy subjects of similar age and sex were compared. Endothelium-dependent and independent function were evaluated by ultrasonic measurement of flow-mediated dilatation (FMD) and glyceryl trinitrate (GTN)-induced dilatation of the brachial artery respectively. Vascular compliance was assessed by carotid-femoral pulse wave velocity (PWV) and augmentation index (AIx). Heart failure severity was similar in IHD and DCM patients. FMD was impaired in the subjects with IHD as compared with control subjects (4.8 +/- 0.3 vs. 8.0 +/- 3.6 %, P < .01), but not in those with DCM. GTN-induced vasodilatation was not different in patients and controls. PWV was also increased in IHD patients compared with controls (12.1 +/- 3.6 vs. 8.0 +/- 1.6 m/s, P < .01), but not in DCM patients. AIx was similar in patients and controls. CONCLUSION: Heart failure of nonischemic etiology is not associated with abnormalities of endothelium-mediated dilatation or of arterial compliance. The findings of our study now need to be confirmed in larger studies.

Differential effects of beta-adrenoreceptor antagonists on central and peripheral blood pressure at rest and during exercise.

BACKGROUND: Differential effects of beta-adrenoreceptor antagonists (beta-ARB) on central and peripheral blood pressure may relate to change in heart rate and/or vasodilator tone and thus be exaggerated during exercise. AIMS: To examine acute effects of selective and nonselective beta-ARB on central and peripheral blood pressure, cardiac output and peripheral vascular resistance during exercise. METHODS: Healthy volunteers (n= 20, 18 men, 19-54 years) received propranolol 80 mg, bisoprolol 20 mg, and placebo 1 h before bicycle ergometry (50, 75 and 100 W each for 3 min) in a randomized, cross-over study. Cardiac output was determined by pulmonary uptake of soluble and inert gas tracers (InnoCor, Innovision). Central systolic blood pressure (SBP) was determined from the late systolic shoulder of the digital artery pressure waveform (Finometer, Finopres). RESULTS: At rest, both beta-ARB reduced brachial but not central SBP (compared with placebo). During exercise, beta-ARB reduced brachial SBP (reductions of 19.9 +/- 4.3 mmHg and 23.2 +/- 2.7 mmHg for propranolol and bisoprolol, respectively, at 100 W, each P < 0.0001) but not central SBP. The difference between peripheral and central SBP was reduced, relative to that during placebo, by 21.5 mmHg (95% confidence interval 8.8, 34.1) and 26.4 mmHg (18.1, 34.8) for propranolol and bisoprolol, respectively, at 100 W (each P < 0.01). There was no significant effect of beta-ARB on diastolic blood pressure or peripheral vascular resistance. CONCLUSIONS: Despite reducing brachial blood pressure, acute beta-adrenoreceptor blockade in man at rest and during exercise does not reduce central blood pressure.

A Randomized, Double-Blind, Placebo-Controlled, First-Time-in-Human Study to Assess the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of GSK3389404 in Healthy Subjects.

GSK3389404 is a liver-targeted antisense oligonucleotide that inhibits synthesis of hepatitis B surface antigen and all other hepatitis B virus proteins. This first-in-human, randomized, double-blind, phase 1 study assessed the safety and pharmacokinetics of GSK3389404 administered subcutaneously (SC) in healthy subjects. Four single ascending-dose cohorts (10 mg, 30 mg, 60 mg, and 120 mg) and 3 multiple ascending-dose cohorts (30 mg, 60 mg, and 120 mg once weekly for 4 weeks) each comprised 6 subjects randomized to GSK3389404 and 2 subjects randomized to placebo. There were no serious adverse events (AEs) or withdrawals due to AEs. The safety profile did not worsen with repeated dosing. The most frequent treatment-related AEs were injection site reactions (19.0% [n = 8/42], frequency unrelated to dose levels); all were mild (Grade 1) and resolved without dose modification or discontinuation. GSK3389404 administered subcutaneously was readily absorbed with a time to maximum plasma concentration (Tmax ) of 1-4 hours and an elimination half-life of 3-6 hours in plasma. Plasma area under the concentration-time curve (AUC) and maximum observed concentration (Cmax ) were dose-proportional. Dose-normalized plasma AUC from time 0 to infinity averaged 69.9 ng·h/(mL·mg dose) across cohorts, and Cmax 9.5 ng/(mL·mg dose). Pharmacokinetic profiles and parameters were comparable between single and multiple dosing. No accumulation was observed with once-weekly dosing. The metabolite was undetectable in urine and plasma. In the pooled urine, GSK3389404 was estimated to account for <0.1% of the total dose. In summary, GSK3389404 dosing has been tested up to 120 mg for 4 weeks with an acceptable safety and pharmacokinetic profile, supporting further clinical investigation in patients with chronic hepatitis B.

Assessment of endothelial function: comparison of the pulse wave response to beta 2-adrenoceptor stimulation with flow mediated dilatation.

AIMS: To assess the reproducibility of the digital pulse wave response to beta(2)-adrenoreceptor stimulation and to determine if an attenuated response to beta(2)-adrenoceptor stimulation is associated with impaired flow mediated dilatation (FMD). METHODS: Subjects (n = 20) with endothelial dysfunction (ED), were compared with healthy control subjects (n = 20). Change in reflection index (Delta RI) of the digital volume pulse in response to salbutamol (SALB, 5 microg min(-1) i.v) and to nitroglycerin (NTG, 5 microg min(-1) i.v) was used to assess endothelium-dependent (Delta RI(SALB)) and endothelium-independent (Delta RI(NTG)) pressure wave reflection. Delta RI(SALB) was assessed on two occasions to examine reproducibility. High resolution ultrasound of the brachial artery was used to measure FMD and also dilation to NTG (NTGD). RESULTS: The mean difference in Delta RI(SALB) between two visits was -0.2%, with SD of the difference 4.9%. Both Delta RI(SALB) and FMD were impaired in subjects with ED compared with values in control subjects (5.0 +/- 0.7 vs. 11.3 +/- 1.2%, mean values +/- SEM, P < 0.01 and 4.2 +/- 0.6 vs. 7.5 +/- 0.8%, P < 0.02 for Delta RI(SALB) and FMD, respectively), whereas Delta RI(NTG) and NTGD were similar in the two groups. Delta RI(SALB) was correlated with FMD (r = 0.44, P < 0.01) and had 88% sensitivity and 79% specificity to detect abnormal (FMD < 4%). CONCLUSIONS: The pulse wave response to a beta(2)-adrenoceptor agonist correlates with FMD and has high sensitivity and specificity in detecting abnormal endothelial function as defined by FMD. However, FMD is the preferred test to detect effects of interventions on endothelial function.

Repeat doses of antibody to serum amyloid P component clear amyloid deposits in patients with systemic amyloidosis.

Systemic amyloidosis is a fatal disorder caused by pathological extracellular deposits of amyloid fibrils that are always coated with the normal plasma protein, serum amyloid P component (SAP). The small-molecule drug, miridesap, [(R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC)] depletes circulating SAP but leaves some SAP in amyloid deposits. This residual SAP is a specific target for dezamizumab, a fully humanized monoclonal IgG1 anti-SAP antibody that triggers immunotherapeutic clearance of amyloid. We report the safety, pharmacokinetics, and dose-response effects of up to three cycles of miridesap followed by dezamizumab in 23 adult subjects with systemic amyloidosis (ClinicalTrials.gov identifier: NCT01777243). Amyloid load was measured scintigraphically by amyloid-specific radioligand binding of 123I-labeled SAP or of 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid. Organ extracellular volume was measured by equilibrium magnetic resonance imaging and liver stiffness by transient elastography. The treatment was well tolerated with the main adverse event being self-limiting early onset rashes after higher antibody doses related to whole body amyloid load. Progressive dose-related clearance of hepatic amyloid was associated with improved liver function tests. 123I-SAP scintigraphy confirmed amyloid removal from the spleen and kidneys. No adverse cardiac events attributable to the intervention occurred in the six subjects with cardiac amyloidosis. Amyloid load reduction by miridesap treatment followed by dezamizumab has the potential to improve management and outcome in systemic amyloidosis.