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.

Theoretical Analysis of the Pressure Regions Where Adsorption Azeotropes Exist in Binary Gas Mixtures.

This work confirmed theoretically whether adsorption azeotropes can form in a binary gas mixture at a pressure P below the intersection pressure of the corresponding single-gas isotherms. The thermodynamically consistent dual-process Langmuir (DPL) model with equal component i saturation capacities q i, j s on site j and the general DPL model with nonequal q i, j s on site j were used for this purpose. Relationships derived from both DPL models, in terms of the single-gas isotherm DPL model parameters, were used to answer this question. When the P range where adsorption azeotropes always exist is infinite beyond the onset P of adsorption azeotropic formation, both DPL models and experimental data showed that it is possible to form adsorption azeotropes in the corresponding binary gas mixture at pressures not only above but even below the single-gas isotherm intersection P. When the P range where adsorption azeotropes always exist is finite beyond the onset P of adsorption azeotropic formation, only the general DPL model predicts the onset P of this finite P range can be below the intersection P of the corresponding single-gas isotherms. Without theoretical proof, the thermodynamically consistent DPL model seemingly restricts this P range to be equal to or greater than the intersection P of the corresponding single-gas isotherms. For a finite P region where adsorption azeotropes always exist in a binary gas mixture, the binary selectivity inverts when traversing from below the lower onset P to the higher cessation P. Both models also showed, counterintuitively, that perfect positive energetic site matching can result in the formation of adsorption azeotropes in binary gas mixtures, not just perfect negative energetic site matching. Overall, this work provides some confirmation that it is indeed possible to form adsorption azeotropes in a binary gas mixture at pressures below the intersection P of the corresponding single-gas isotherms based on two physically sound formulations of the DPL model.

Theoretical Analysis of the Necessary and Sufficient Conditions for the Formation of Adsorption Azeotropes in Binary Gas Mixtures.

This work theoretically assessed the necessary and sufficient conditions for the formation of an adsorption azeotrope in a binary gas mixture when this mixture exhibits either intersecting or nonintersecting single gas isotherms. The thermodynamically consistent dual process Langmuir (DPL) model with equal component i saturation capacities qi,js on site j and the general DPL model with nonequal qi,js on site j were used for this purpose. Analytical expressions derived for both DPL models, in terms of the single gas isotherm DPL model parameters, were used to find examples or to determine theoretically when an adsorption azeotrope forms in a binary gas mixture for both intersecting and nonintersecting single gas isotherms. For the general DPL model, it was determined that neither necessary nor sufficient conditions exist for the formation of an adsorption azeotrope in a binary gas mixture. This means that an adsorption azeotrope can form irrespective of whether the corresponding single gas isotherms intersect or not. For the thermodynamically consistent DPL model, it was determined that the intersection of the single gas isotherms is a sufficient condition for the formation of an adsorption azeotrope in a binary gas mixture, but it is not a necessary condition. This means that intersecting single gas isotherms guarantee the formation of an adsorption azeotrope in the corresponding binary gas mixture, while nonintersecting single gas isotherms can also result in the formation of an adsorption azeotrope in the corresponding binary gas mixture. Overall, this analysis provides a well-posed resolution to the question of necessity and sufficiency for the formation of adsorption azeotropes in binary gas mixtures and the intersection of their corresponding single gas isotherms based on two physically sound formulations of the very popular DPL model.

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.

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.

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.

Limitations of Breakthrough Curve Analysis in Fixed-Bed Adsorption.

This work examined in detail the a priori prediction of the axial dispersion coefficient from available correlations versus obtaining both it and mass transfer information from experimental breakthrough data and the consequences that may arise when doing so based on using a 1-D axially dispersed plug flow model and its associated Danckwerts outlet boundary condition. These consequences mainly included determining the potential for erroneous extraction of the axial dispersion coefficient and/or the LDF mass transfer coefficient from experimental data, especially when nonplug flow conditions prevailed in the bed. Two adsorbent/adsorbate cases were considered, i.e., CO2 and H2O vapor in zeolite 5A, because they both experimentally exhibited significant nonplug flow behavior, and the H2O-zeolite 5A system exhibited unusual concentration front sharpening that destroyed the expected constant pattern behavior (CPB) when modeled with the 1-D axially dispersed plug flow model. Overall, this work showed that it was possible to extract accurate mass transfer and dispersion information from experimental breakthrough curves using a 1-D axial dispersed plug flow model when they were measured both inside and outside the bed. To ensure the extracted information was accurate, the inside the bed breakthrough curves and their derivatives from the model were plotted to confirm whether or not the adsorbate/adsorbent system was exhibiting CPB or any concentration front sharpening near the bed exit. Even when concentration front sharpening was occurring with the H2O-zeolite 5A system, it was still possible to use the experimental inside and outside the bed breakthrough curves to extract fundamental mass transfer and dispersion information from the 1-D axial dispersed plug flow model based on the systematic methodology developed in this work.

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.).

Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to LDL receptors, leading to their degradation. Genetics studies have shown that loss-of-function mutations in PCSK9 result in reduced plasma LDL cholesterol and decreased risk of coronary heart disease. We aimed to investigate the safety and efficacy of ALN-PCS, a small interfering RNA that inhibits PCSK9 synthesis, in healthy volunteers with raised cholesterol who were not on lipid-lowering treatment. METHODS: We did a randomised, single-blind, placebo-controlled, phase 1 dose-escalation study in healthy adult volunteers with serum LDL cholesterol of 3·00 mmol/L or higher. Participants were randomly assigned in a 3:1 ratio by computer algorithm to receive one dose of intravenous ALN-PCS (with doses ranging from 0·015 to 0·400 mg/kg) or placebo. The primary endpoint was safety and tolerability of ALN-PCS. Secondary endpoints were the pharmacokinetic characteristics of ALN-PCS and its pharmacodynamic effects on PCSK9 and LDL cholesterol. Study participants were masked to treatment assignment. Analysis was per protocol and we used ANCOVA to analyse pharmacodynamic endpoint data. This trial is registered with ClinicalTrials.gov, number NCT01437059. FINDINGS: Of 32 participants, 24 were randomly allocated to receive a single dose of ALN-PCS (0·015 mg/kg [n=3], 0·045 mg/kg [n=3], 0·090 mg/kg [n=3], 0·150 mg/kg [n=3], 0·250 mg/kg [n=6], or 0·400 mg/kg [n=6]) and eight to placebo. The proportions of patients affected by treatment-emergent adverse events were similar in the ALN-PCS and placebo groups (19 [79%] vs seven [88%]). ALN-PCS was rapidly distributed, with peak concentration and area under the curve (0 to last measurement) increasing in a roughly dose-proportional way across the dose range tested. In the group given 0·400 mg/kg of ALN-PCS, treatment resulted in a mean 70% reduction in circulating PCSK9 plasma protein (p<0·0001) and a mean 40% reduction in LDL cholesterol from baseline relative to placebo (p<0·0001). INTERPRETATION: Our results suggest that inhibition of PCSK9 synthesis by RNA interference (RNAi) provides a potentially safe mechanism to reduce LDL cholesterol concentration in healthy individuals with raised cholesterol. These results support the further assessment of ALN-PCS in patients with hypercholesterolaemia, including those being treated with statins. This study is the first to show an RNAi drug being used to affect a clinically validated endpoint (ie, LDL cholesterol) in human beings. FUNDING: Alnylam Pharmaceuticals.