Pharmacokinetics of BC 007
The mean plasma BC 007 concentration–time profiles of all single cohorts of Parts A, B and C are depicted in Figs. 2, 3, 4 in a semi-logarithmic scale.
The main information obtained from a visual inspection of the plasma concentration–time curves following administration of 15, 50 and 150 mg infusions over 20 min (Part A, Fig. 2) was the rapid increase in concentrations with comparable highest concentrations for the 150 mg dose level, whether receiving a bolus dose or not. For the 15 mg dose level, the highest concentration was observed for the bolus group and the reverse was observed for the 50 mg dose.
The main information from a visual inspection of the plasma concentration–time curves following administration of 50 and 150 mg infusions over 20 min in elderly male and female subjects was, comparable to the Part A results, an obvious rapid increase of concentrations with comparable highest concentrations, whether receiving a bolus dose or not at 50 mg (Fig. 3a) and highest concentrations for the subjects without a bolus at 150 mg (Fig. 3b).
Concentrations of BC 007 declined rapidly with all dose levels below the quantifiable limit at 2-h post-dose.
The main information from a visual inspection of the BC 007 plasma concentration–time curves following administration of 300, 450 and 750 mg with a bolus (150 mg each) and without a bolus (40 min infusion), and 1350 mg (75 min) and 1900 mg (105 min) infusions only showed, comparable to Parts A and B, a rapid increase in concentrations with comparable highest concentrations for the 750 mg dose level, whether receiving a bolus dose or not (Fig. 4c). For the 300 and 450 mg dose levels, the mean highest concentration for doses with a bolus were higher than without a bolus (Fig. 4a, b). This was all expected, given the different proportion of dose administered as a bolus. At doses of 300 mg and 450 mg with a bolus, the plasma concentrations of BC 007 declined rapidly below the quantifiable limit at 2-h post-dose and at 450 mg without a bolus at 4-h post-dose. For the 750 and 1350 mg doses without a bolus, the concentrations were below the quantifiable limit by 2-h and 4-h post-dose, respectively. Concentrations were measured for at least one subject through 8-h post-dose for the 750 mg with a bolus and through 4-h post-dose for the 1900 mg.
Plasma pharmacokinetic parameters for all study participants of Parts A, B and C are given in Table 2.
Across all study parts, including a steadily increasing dose (15–1900 mg) and infusion time (20–105 min) and also different dosing regimen (with and without bolus), Tmax covered an expected range between 1–25 min.
The mean Cmax values increased with the dose and ranged in Part A (15–150 mg) from 1755 to 7566 ng/mL (with bolus) and 858 to 9051 ng/mL (without bolus); in Part B (50 mg, 150 mg) 2931 and 7625 ng/mL (with bolus) and 2389 and 8495 ng/mL (without bolus); in Part C (300, 450, 750 mg) from 19,931 to 20,370 ng/mL (with bolus) and 9453 to 15,415 ng/mL (without bolus), and at 1350 and 1900 mg without bolus from 18,833 to 22,207 ng/mL.
The mean AUC(0–24) values increased with the dose and ranged in Part A (15–150 mg) from 381 to 2209 h·ng/mL (with bolus) and 262 to 2698 h·ng/mL (without bolus); in Part B (50 mg, 150 mg) 631 and 1665 h·ng/mL (with bolus) and 742 and 2105 h·ng/mL (without bolus); in Part C (300, 450, 750 mg) from 5717 to 9782 h·ng/mL (with bolus) and 5709 to 8974 h·ng/mL (without bolus) and at 1350 and 1900 mg without bolus from 18,977 and 28,678 h·ng/mL.
The elimination half-life was generally short and amounted to dose-dependent increasing values between 2.9 min in the young population at lower doses and infusion rates and 11 min in the elderly population at higher doses and infusion rates, neglecting the different dosing routines. The increase in half-life with dose is likely to be dependent on the possibility of a subsequent elimination phase for a longer time at higher doses while at lower doses the half-life might be more representative of the distribution phase.
BC 007 Dose Proportionality
The relationship between AUC and dose was assessed using a power model to fit the natural logarithm of the parameter to the natural logarithm of the dose for the data of Parts B and C of the study. All data of all doses with or without bolus were included; the plot for AUC(0–t) is depicted in Fig. 5.
Slope estimates revealed that the parameters AUC(0-t) and AUC(0–inf) (data not shown) increased in a dose-proportional manner across the dose range 50–1900 mg, showing slope estimates of 1.0390 (95% CI 0.9578–1.1202) and 1.0388 (95% CI 0.9563–1.1214), respectively.
With respect to C0, this parameter was affected by the increase in concentration of bolus by parallel infusion. A proper assessment of dose proportionality of C0 would require a bolus dose in the absence of infusion. The more than dose-proportional increase of the slope estimate of C0 of 1.8051 across the dose range 50–750 mg administered with a bolus, has to be, therefore, considered with caution.
Additionally, because of the change of infusion time, a power model for Cmax has not been reported.
BC 007 Urine Concentration
The fraction of the dose (fe (0–24)) excreted unchanged in urine in 24 hrs after dosing was less than 0.01% for all treatments (see Table 3). Renal clearance (CLR) was estimated to range from 0.0093 to 0.098 mL/min for doses with a bolus and 0.0 to 0.2 mL/min for subjects receiving doses without a bolus (Part A), 0.062 and 0.1 mL/min for 50 and 150 mg doses with a bolus and 0.025 and 0.055 mL/min for subjects receiving the same doses without a bolus, respectively (Part B), and 0.19 to 0.82 mL/min for doses with a bolus and 0.14 to 2.8 mL/min for subjects receiving doses without a bolus (Part C).
BC 007 Metabolites (n–x)
According to Shaw et al. who investigated an ex vivo successive 3′-exonuclease degradation in monkey plasma and serum , the n–x degradation was investigated as an exploratory parameter. In the current study, at higher doses of BC 007, a 3′-exonuclease degradation was detectable down to n-3 and amounted in total to about 7% of the plasma concentration of full-length BC 007, exemplarily shown for 1900 mg BC 007 in Fig. 6.
N-1 was the major metabolite of the 3′-exonulease products with an AUC0–t of 1116.3 and 1542.9 h·ng/mL at a dose of 1350 and 1900 mg BC 007, respectively. Comparable to the parent compound, the concentration declined quickly after stopping the infusion, showing a t1/2 of about 8 min.
fGPCR-AAb Status After Dosing (Mode of Action)
The fGPCR-AAb neutralisation effect showed a clear tendency of a dose–effect relationship, as shown in Table 4.
At a dose of 1900 mg BC 007 given as an infusion over 105 min the fGPCR-AAbs were neutralised in all six treated subjects one month after dosing. At lower doses, the share of successfully fGPCR-AAb neutralised patients in the total number of treated patients was lower, as shown in Table 4. A more detailed breakdown according to the single fAAb subtypes can be taken from Müller et al. .
BC 007 Safety
No treatment emergent adverse event (TEAE) leading to subject discontinuation, no severe TEAEs, no serious adverse events (SAEs) and no deaths were reported throughout the entire clinical Phase I.
The most common reported adverse event was a slight-to-moderate anticoagulatory effect accompanying the infusion and seen via increased activated partial thromboplastin time (aPTT), increased prothrombin time (PT) and increased international normalised ratio (INR). This was due to the fact that the sequence of BC 007 was originally selected as a potential short-lasting thrombin inhibitor for transient anticoagulation during coronary bypass graft surgery. However, in this indication it was not successful because the lack of a persistent effect resulted in a suboptimal dosing profile; too high a dose for a therapeutic effect. This anticoagulatory effect was observed in all cohorts, beginning at a dose of 50 mg. The anticoagulatory effect normalised quickly, within minutes after the end of the infusion.
Besides this anticoagulatory effect, the following were recorded:
In Part A (24 treated subjects), no clinically significant changes in vital signs, ECG and temperature assessments were observed. Throughout all cohorts of this study part (15–150 mg BC 007), two subjects showed slightly elevated alanine aminotransferase and two subjects showed slightly elevated aspartate amino transferase. One subject reported mild palpitations and another subject a mild headache, both assessed as possibly related to investigational medical product (IMP).
In Part B (12 treated subjects, 50 and 150 mg), no clinically significant changes in vital signs, ECG and temperature assessments were observed. No adverse events with a possible relation to IMP were reported, except the above-mentioned anticoagulatory effect.
In Part C (300, 450, 750, 1350 mg and 1900 mg BC 007, Cohorts 1–5, altogether 30 treated subjects), no clinically significant changes in vital signs and temperature assessments were observed, except for one subject in Cohort 3 who showed elevated systolic and diastolic blood pressure on several measurements, which were, however, unrelated to infusion of BC 007. No clinically significant ECG changes or post-dose trends were observed in any subjects. One subject in Cohort 3 showed a QRS angle between − 15 and − 50 in all ECGs, unrelated to infusion of BC 007. ECGs with values between − 35° and − 50° were assessed as left anterior hemi block, being not clinically relevant.
Further, a first-degree atrioventricular (AV) block in one subject of Cohort 2, a first-degree AV block in another subject and prolonged QTcB/F in one subject of Cohort 4 and first degree AV block in one subject of Cohort 5, left anterior hemi block in another subject were recorded. However, all these findings were assessed as: a) not clinically relevant; and b) not related to BC 007. One subject in Cohort 1 experienced mild dizziness with a possible relation to IMP. One had mild loose stool and a third moderate nausea after the end of the bolus injection. In Cohort 4 (1350 mg), sleepiness of mild intensity in one subject was recorded. In Cohort 5 (1900 mg), four out of the six subjects experienced four AEs assessed as possibly related to IMP. However, all were the before-mentioned moderately prolonged aPTT.
In all subjects of Cohorts 4 and 5 (1350 and 1900 mg), an increase in uric acid was seen, beginning 50 min after the start of the infusion, with peak values at 120 and 110 min after the start of the infusion, respectively, with only slight elevation left on Day 2 and complete return to baseline on Day 8. This increase was within the normal physiologic range .
Placebo data from all cohorts were pooled within each age group (young: Cohorts 1–3 or elderly: Cohort 4) for safety analyses. One subject of the younger group experienced mild headache, an unrelated TEAE.