A Phase I Randomized Study of a Specifically Engineered, pH-Sensitive PCSK9 Inhibitor RN317 (PF-05335810) in Hypercholesterolemic Subjects on Statin Therapy.

This phase I study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of RN317 (PF-05335810), a specifically engineered, pH-sensitive, humanized proprotein convertase subtilisin kexin type 9 (PCSK9) monoclonal antibody, in hypercholesterolemic subjects (low-density lipoprotein cholesterol (LDL-C) ≥ 80 mg/dl) 18-70 years old receiving statin therapy. Subjects were randomized to: single-dose placebo, RN317 (subcutaneous (s.c.) 0.3, 1, 3, 6, or intravenous (i.v.) 1, 3, 6 mg/kg), or bococizumab (s.c. 1, 3, or i.v. 1 mg/kg); or multiple-dose RN317 (s.c. 300 mg every 28 days; three doses). Of 133 subjects randomized, 127 completed the study. RN317 demonstrated a longer half-life, greater exposure, and increased bioavailability vs. bococizumab. RN317 was well tolerated, with no subjects discontinuing because of treatment-related adverse events. RN317 lowered LDL-C by up to 52.5% (day 15) following a single s.c. dose of 3.0 mg/kg vs. a maximum of 70% with single-dose bococizumab s.c. 3.0 mg/kg. Multiple dosing of RN317 produced LDL-C reductions of ∼50%, sustained over an 85-day dosing interval.

In search of physiologically based distribution volume estimates for macromolecules.

In their semimechanistic analysis of trastuzumab emtansine (T-DM1) pharmacokinetics, Chudasama et al., as reported in this issue, modeled the process of T-DM1 deconjugation with a series of transit compartments representing plasma volume and a single peripheral compartment. The implausibility of the two-compartment distribution model used in this study as well as in other recent attempts to analyze the distribution kinetics of trastuzumab and other macromolecules reflects the fact that this modeling has been guided primarily by statistical rather than physiological considerations.

Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies.

A Phase I dose escalation trial of i.v. administered recombinant human interleukin 12 (rhIL-12) was performed to determine its toxicity, maximum tolerated dose (MTD), pharmacokinetics, and biological and potential antineoplastic effects. Cohorts of four to six patients with advanced cancer, Karnofsky performance >/=70%, and normal organ function received escalating doses (3-1000 ng/kg/day) of rhIL-12 (Genetics Institute, Inc.) by bolus i.v. injection once as an inpatient and then, after a 2-week rest period, once daily for five days every 3 weeks as an outpatient. Therapy was withheld for grade 3 toxicity (grade 4 hyperbilirubinemia or neutropenia), and dose escalation was halted if three of six patients experienced a dose-limiting toxicity (DLT). After establishment of the MTD, eight more patients were enrolled to further assess the safety, pharmacokinetics, and immunobiology of this dose. Forty patients were enrolled, including 20 with renal cancer, 12 with melanoma, and 5 with colon cancer; 25 patients had received prior systemic therapy. Common toxicities included fever/chills, fatigue, nausea, vomiting, and headache. Fever was first observed at the 3 ng/kg dose level, typically occurred 8-12 h after rhIL-12 administration, and was incompletely suppressed with nonsteroidal anti-inflammatory drugs. Routine laboratory changes included anemia, neutropenia, lymphopenia, hyperglycemia, thrombocytopenia, and hypoalbuminemia. DLTs included oral stomatitis and liver function test abnormalities, predominantly elevated transaminases, which occurred in three of four patients at the 1000 ng/kg dose level. The 500 ng/kg dose level was determined to be the MTD. This dose, administered by this schedule, was associated with asymptomatic hepatic function test abnormalities in three patients and an onstudy death due to Clostridia perfringens septicemia but was otherwise well tolerated by the 14 patients treated in the dose escalation and safety phases. The T1/2 elimination of rhIL-12 was calculated to be 5.3-9.6 h. Biological effects included dose-dependent increases in circulating IFN-gamma, which exhibited attenuation with subsequent cycles. Serum neopterin rose in a reproducible fashion regardless of dose or cycle. Tumor necrosis factor alpha was not detected by ELISA. One of 40 patients developed a low titer antibody to rhIL-12. Lymphopenia was observed at all dose levels, with recovery occurring within several days of completing treatment without rebound lymphocytosis. There was one partial response (renal cell cancer) and one transient complete response (melanoma), both in previously untreated patients. Four additional patients received all proposed treatment without disease progression. rhIL-12 administered according to this schedule is biologically and clinically active at doses tolerable by most patients in an outpatient setting. Nonetheless, additional Phase I studies examining different schedules and the mechanisms of the specific DLTs are indicated before proceeding to Phase II testing.

Recombinant human factor IX: replacement therapy, prophylaxis, and pharmacokinetics in canine hemophilia B.

Recombinant human factor IX (rFIX) has been expressed in transduced cultured cell systems since 1985. Because there has been limited in vivo testing of rFIX in hemophilia B subjects, this study was undertaken using the severe hemophilia B canines of the Chapel Hill strain. Three groups of hemophilic dogs received either 50, 100, or 200 IU/kg of rFIX. As a control, a fourth group of hemophilic dogs received 50 IU/kg of a high purity, plasma-derived human FIX (pdFIX). The coagulant and hemostatic effects of rFIX and pdFIX were similar with all comparative dosing regimens. Based on activity data, the elimination half-life of rFIX was 18.9 +/- 2.3 hours and pdFIX was 17.9 +/- 2.1 hours. A prophylactic regimen administering rFIX daily resulted in a continuous therapeutic level of plasma FIX and was accompanied by a two-fold increase in recovery levels by day 5, compared to that observed with administration of a single bolus. The mechanisms of the high to complete recovery of FIX with the prophylactic regimen could depend not only on the degree of saturation of the vascular endothelial binding sites but also on the altered dynamics of the balance of FIX distribution between the intravascular and extravascular compartments. The pharmacokinetic (PK) parameters for rFIX and pdFIX were similar. However, the relative PK values for V1 and V5s of both products on day 5 differed greatly from day 1 and may reflect the changing equilibrium of FIX between compartments with elevated levels of plasma FIX. Neutralizing antihuman FIX antibodies resulting from human FIX antigen being administered to FIX deficient dogs were observed beginning at 14 days. The antigenicity of rFIX and pdFIX appeared to be comparable. Despite the very different procedures used for production of rFIX and pdFIX products, in vivo testing in hemophilia B dogs showed the functional behavior of these products is similar; they are highly effective for replacement therapy and for prophylaxis.

Comparison of the spectrum of cognitive effects of alprazolam and adinazolam after single doses in healthy subjects.

Single doses of alprazolam (0, 0.5, 1.5 mg) or adinazolam mesylate sustained release tablets (SR) (0, 15, 45 mg) were administered to separate groups of 12 healthy men in a crossover design. Psychomotor performance was assessed by digit symbol substitution (DSST), and memory was assessed using a test battery which reflects various aspects of memory, including attention/working memory, explicit memory (recall of categorically related words), semantic memory (fragmented picture recognition, generation of category exemplars), and implicit memory (time saved in resolving fragmented pictures on the second exposure). Maximal psychomotor performance and memory decrements for the highest active doses were significantly different from placebo for all tasks at some time after dosing. The maximum decrement in DSST was not significantly different between drugs at the high dose (P = 0.288). Maximum attention/working memory decrements were significantly different between the high doses of the active compounds (P = 0.031), and the difference in maximum category recall decrement was marginally significant (P = 0.067). Access to knowledge memory was not significantly altered by these drugs; these results are similar to those obtained for other benzodiazepines. Both drugs exhibited slight effects on implicit memory. The results suggest that the sedative and memory effects of these triazolobenzodiazepines may not be closely related and suggest that adinazolam has a somewhat different spectrum of cognitive effects relative to alprazolam.

Pain perception and serum beta-endorphin in trauma patients.

Acute traumatic injury engenders the production of beta-endorphin (BE) and other endogenous opioids. Elevated BE concentration putatively correlates with pain perception in trauma patients. The authors examined traumatic injury severity, pain perception, and BE concentration in patients admitted to an urban trauma center. Brief rating instruments for pain and unpleasantness were administered, and blood was drawn for BE analysis in 48 trauma admissions and 33 age-, gender-, and race-matched control subjects for comparison. The authors found no correlation between severity of pain perception and BE, but a significant correlation was found between BE and patient body weight (P < 0.05), physician pain rating (P < 0.01), and Injury Severity Score (P < 0.001). The results suggest that past findings associating trauma pain perception and BE concentration are spurious.

Pharmacokinetics of the newer benzodiazepines.

The assay methods used to determine the concentrations of the newer benzodiazepines include electron-capture gas-liquid chromatography, high performance liquid chromatography with ultraviolet detection, gas chromatography-mass spectrometry, radioassay and radioreceptor assay. The method used frequently is the highly sensitive and specific electron-capture gas-liquid chromatography. Other methods are associated with limitations. The triazolo- and imidazolebenzodiazepines differ structurally from the 'classical' benzodiazepines such as diazepam, and offer distinct differences in pharmacological activity and in time-course of effect. Alprazolam and triazolam, both 1,4-triazolobenzodiazepines, have high affinities for the benzodiazepine receptor as do midazolam and loprazolam, which are 1,4-imidazolebenzodiazepines. Absorption is characteristically rapid, with peak alprazolam and triazolam concentrations occurring within 1 hour after oral administration. Sublingual administration results in peak alprazolam and triazolam concentrations that are higher and occur earlier than with the oral route. The volume of distribution of alprazolam and triazolam is approximately 1L. Alprazolam is 70% bound to plasma proteins and the extent of binding is independent of concentration. Similarly, triazolam is approximately 85% bound to plasma proteins, variability in binding being explained by variations in alpha 1-acid glycoprotein concentration. The 1,4-triazolo ring prevents the oxidative metabolism of the classical benzodiazepines which results in formation of active metabolites with long elimination half-lives. Alprazolam is extensively metabolised: 29 metabolites have been identified in the urine, and its major metabolite, alpha-hydroxyalprazolam, has pharmacological activity. alpha-Hydroxyalprazolam and 4-hydroxyalprazolam are detectable in plasma in amounts which account for less than 10% of the administered dose. Mean alprazolam elimination half-life in healthy adult subjects ranges from 9.5 to 12 hours; liver disease prolongs alprazolam elimination, but renal insufficiency does not. Triazolam also undergoes oxidation and subsequent glucuronidation. alpha-Hydroxytriazolam is the major metabolite, in addition to which 4-hydroxyalprazolam and alpha-4-hydroxytriazolam have been identified in plasma and urine. The elimination half-life of triazolam ranges between 1.8 and 5.9 hours, while that of the conjugated metabolites is short, approximately 3.8 hours. Accumulation of triazolam or its metabolites after multiple doses does not occur. Liver disease prolongs triazolam elimination from the body, but renal disease does not.(ABSTRACT TRUNCATED AT 400 WORDS)