Abiraterone decanoate (AD): Potent and long-acting activity of a novel intramuscular (IM) abiraterone prodrug depot in a castrate monkey model.

78 Background: Oral abiraterone acetate (AA) is a standard of care for castration-resistant (CRPC) and castration-sensitive prostate cancer (CSPC). Due to poor oral bioavailability, the recommended AA dose is 1,000 mg (4 x 250mg) once-daily on an empty stomach. The daily oral regimen produces high peak plasma concentrations that may be associated with safety issues (e.g., hepatotoxicity) and low trough concentrations that may be associated with inadequate CYP17 inhibition. AD is one of a series of novel abiraterone prodrugs that were designed to provide a controlled release of abiraterone and long-acting CYP17 inhibition with IM delivery. Following successful preclinical pilot studies, AD was further developed into a clinically acceptable formulation (PRL-02) and its PK/PD characteristics were evaluated and compared to oral AA in a castrate monkey pharmacology model in support of future clinical development. Methods: Sexually mature male cynomolgus monkeys underwent chemical castration using Lupron depot. Plasma samples were analyzed for prodrug, abiraterone and steroid concentrations following a single oral AA dose (5, 15 or 45 mg/kg) and a single IM AD injection (10, 30 or 100 mg/kg) (n=3/dose group). The combined activity of IM AD plus glucocorticoid replacement (single 0.5 mg/kg IM dexamethasone (DEX) dose or weekly doses of 1.29 mg/kg IM methylprednisolone acetate (MPA)) was also evaluated. AD, abiraterone and adrenal steroid levels were evaluated by LC-MS/MS. Results: Chemical castration resulted in a plasma testosterone (T) decrease of 72% from intact. T was further reduced to sub-castrate levels by both AA and AD (98.6% and 99.7% maximum decrease from castrate baseline, respectively). All dose levels of AD were highly effective in reducing plasma T yet led to abiraterone plasma concentrations (Cmax, AUC, Cmin) that were much less than those associated with steady-state clinical levels from oral AA. Sustained T suppression was observed following all single AD IM doses for 14 weeks, the last timepoint tested.The addition of a glucocorticoid replacement (DEX or MPA) starting at week 9 further reduced T in all AD groups. Conclusions: Single-dose IM AD suppressed T to the same or greater extent than single-dose oral AA in castrate monkeys, while providing much lower abiraterone exposures than the oral acetate prodrug. As such, IM AD may offer an improved risk-benefit profile due to the consistently lower abiraterone levels. The durable, profound T reductions provided by all AD doses are consistent with a 3-month clinical regimen that can be given in conjunction with Lupron. IM AD may thus offer patients with CSPC and CRPC a more convenient, safe and effective alternative than daily oral AA.

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Single-dose pharmacokinetics of orally administered terbinafine in bearded dragons (Pogona vitticeps) and the antifungal susceptibility patterns of Nannizziopsis guarroi

American Journal of Veterinary Research ◽

10.2460/ajvr.21.02.0023 ◽

2021 ◽

pp. 1-8

Author(s):

Michael S. McEntire ◽

Jennifer M. Reinhart ◽

Sherry K. Cox ◽

Krista A. Keller

Keyword(s):

Single Dose ◽

High Performance ◽

Clinical Decision Making ◽

Peak Plasma ◽

Antifungal Susceptibility ◽

Plasma Concentrations ◽

Clinical Decision ◽

Oral Solution ◽

Susceptibility Data ◽

Pogona Vitticeps

Abstract OBJECTIVE To identify the antifungal susceptibility of Nanniziopsis guarroi isolates and to evaluate the single-dose pharmacokinetics of orally administered terbinafine in bearded dragons. ANIMALS 8 healthy adult bearded dragons. PROCEDURES 4 isolates of N guarroi were tested for antifungal susceptibility. A compounded oral solution of terbinafine (25 mg/mL [20 mg/kg]) was given before blood (0.2 mL) was drawn from the ventral tail vein at 0, 4, 8, 12, 24, 48, 72, and 96 hours after administration. Plasma terbinafine concentrations were measured with high-performance liquid chromatography. RESULTS The antifungal minimum inhibitory concentrations against N guarroi isolates ranged from 4,000 to > 64,000 ng/mL for fluconazole, 125 to 2,000 ng/mL for itraconazole, 125 to 2,000 ng/mL for ketoconazole, 125 to 1,000 ng/mL for posaconazole, 60 to 250 ng/mL for voriconazole, and 15 to 30 ng/mL for terbinafine. The mean ± SD peak plasma terbinafine concentration in bearded dragons was 435 ± 338 ng/mL at 13 ± 4.66 hours after administration. Plasma concentrations remained > 30 ng/mL for > 24 hours in all bearded dragons and for > 48 hours in 6 of 8 bearded dragons. Mean ± SD terminal half-life following oral administration was 21.2 ± 12.40 hours. CLINICAL RELEVANCE Antifungal susceptibility data are available for use in clinical decision making. Results indicated that administration of terbinafine (20 mg/kg, PO, q 24 to 48 h) in bearded dragons may be appropriate for the treatment of dermatomycoses caused by N guarroi. Clinical studies are needed to determine the efficacy of such treatment.

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Amino Acid Plasma Profiles from a Prolonged-Release Protein Substitute for Phenylketonuria: A Randomized, Single-Dose, Four-Way Crossover Trial in Healthy Volunteers

Nutrients ◽

10.3390/nu12061653 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1653 ◽

Cited By ~ 1

Author(s):

Mika Scheinin ◽

Anna Barassi ◽

Jouni Junnila ◽

Zsófia Lovró ◽

Giorgio Reiner ◽

...

Keyword(s):

Single Dose ◽

Amino Acid ◽

Healthy Volunteers ◽

Crossover Trial ◽

Peak Plasma ◽

Plasma Concentrations ◽

Prolonged Release ◽

Metabolic Markers ◽

Primary Endpoints ◽

Secondary Endpoints

Several disorders of amino acid (AA) metabolism are treated with a protein-restricted diet supplemented with specific AA mixtures. Delivery kinetics impacts AA absorption and plasma concentration profiles. We assessed plasma profiles after ingestion of an AA mixture engineered to prolong AA absorption with Physiomimic TechnologyTM (Test) in a randomized, single-dose, four-way crossover trial in healthy volunteers (Trial Registration: ISRCTN11016729). In a two-step hypothesis, the primary endpoints were (i) significant reduction in peak plasma concentrations (Cmax) of essential amino acids (EAAs) while (ii) maintaining EAA bioavailability (AUC0-300 min) compared to a free AA mixture (Reference). Secondary endpoints included effects on plasma profiles of other AA groups and effects on several metabolic markers. Thirty subjects completed the study. Both co-primary endpoints were met: Cmax for EAAs was 27% lower with the Test product compared to the Reference product (ratio, 0.726, p < 0.0001); overall plasma EAA levels from the two AA mixtures was within the pre-specified bioequivalence range (AUC0-300min ratio, 0.890 (95% CI: 0.865, 0.915)). These findings were supported by the results of secondary endpoints. Prolongation of AA absorption was associated with modulation of several metabolic markers. It will be important to understand whether this can improve the long-term management of disorders of AA metabolism.

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Dose Finding and Food Effect Studies of a Novel Abiraterone Acetate Formulation for Oral Suspension in Comparison to a Reference Formulation in Healthy Male Subjects

Pharmaceutics ◽

10.3390/pharmaceutics13122171 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2171

Author(s):

Tamás Jordán ◽

Orsolya Basa-Dénes ◽

Réka Angi ◽

János Orosz ◽

Zsolt Ötvös ◽

...

Keyword(s):

Single Dose ◽

Food Effect ◽

Plasma Concentrations ◽

Systemic Exposure ◽

Abiraterone Acetate ◽

Dose Finding ◽

Oral Suspension ◽

Pharmacokinetic Parameters ◽

Synthesis Inhibitor ◽

Androgen Synthesis

Currently approved formulations of the androgen synthesis inhibitor abiraterone acetate (AA) consist of multiple tablets administered daily in a fasted state. Removing the food effect and switching to a suspension formulation is expected to improve the pharmacokinetic profile and facilitate drug administration for patients with late-stage prostate cancer. Two four-sequence, four-period randomized crossover investigations were undertaken to establish the pharmacokinetic profiles of single doses of commercially available Zytiga®, as the reference AA (R-AA), and a novel tablet for oral suspension (TOS). Four single doses of TOS (from 62.5 to 250 mg) were compared in study C01, and two single doses each of TOS (250 mg) and R-AA (1000 mg) were compared under fasted and fed (modified fasted for R-AA) conditions in C02. Plasma concentrations of abiraterone over time were measured, and pharmacokinetic parameters were calculated. Each doubling of the dose of TOS was associated with a greater than 3-fold increase in exposure. A single dose of TOS (250 mg) exhibited similar exposure over 24 h, whether given fasted (625 ng × h/mL) or fed (485 ng × h/mL). A single dose of TOS (250 mg) was associated with higher (fasted, p = 0.028) or equivalent exposure (fed) compared to 1000 mg R-AA fasted (532 ng × h/mL). Substantially higher exposures were seen with 1000 mg R-AA under modified fasted conditions compared to TOS, irrespective of prandial status (p < 0.001). TOS was generally safe and well tolerated in the study. A 250 mg dose of a novel AA formulation for oral suspension demonstrated bioequivalence to 1000 mg R-AA under fasted conditions. This novel TOS formulation also addresses some of the limitations of current AA treatment, including low bioavailability, high variability in systemic exposure and a large food effect. It may offer an alternative for patients with dysphagia or discomfort with swallowing large pills.

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Macrodantin v. standard nitrofurantoin

Drug and Therapeutics Bulletin ◽

10.1136/dtb.12.12.47 ◽

1974 ◽

Vol 12 (12) ◽

pp. 47-48

Keyword(s):

Single Dose ◽

Urinary Tract ◽

Urinary Tract Infections ◽

Peak Plasma ◽

Plasma Concentrations ◽

Nausea And Vomiting ◽

Recommended Dose ◽

Urinary Infections ◽

High Incidence ◽

Tract Infections

Nitrofurantoin is effective in the treatment of acute urinary tract infections, but its usefulness is limited by the high incidence of unwanted effects. When used in the recommended dose of 100 mg four times daily about a quarter of the patients may suffer nausea and vomiting.1 A single dose of 100 mg at night for the prophylaxis of urinary infections2 caused symptoms in 41% of patients.3 These unwanted effects seem to be related to peak plasma concentrations of the drug rather than to its action on the gut.

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Nitrogen Balance after the Administration of a Prolonged-Release Protein Substitute for Phenylketonuria as a Single Dose in Healthy Volunteers

Nutrients ◽

10.3390/nu13093189 ◽

2021 ◽

Vol 13 (9) ◽

pp. 3189

Author(s):

Mika Scheinin ◽

Jouni Junnila ◽

Giorgio Reiner ◽

Anita MacDonald ◽

Ania C. Muntau

Keyword(s):

Single Dose ◽

Nitrogen Balance ◽

Reference Product ◽

Peak Plasma ◽

Plasma Concentrations ◽

Prolonged Release ◽

Test Product ◽

Randomized Controlled ◽

The Difference ◽

Adult Volunteers

Nitrogen balance is the difference between nitrogen excreted as urea and nitrogen ingested, mainly in proteins. Increased circulating concentrations of amino acids (AA) in the bloodstream are usually associated with proportional increases in the production and excretion of urea. Previously, we reported results from a randomized, controlled, single-dose, crossover trial in healthy adult volunteers (n = 30) (Trial Registration: ISRCTN11016729), in which a Test product (prolonged-release AA mixture formulated with Physiomimic Technology™ (PT™)) significantly slowed down the release and reduced the peak plasma concentrations of essential AAs compared with a free AA mixture (Reference product) while maintaining essential AA bioavailability. Here, we report an assessment of the nitrogen balance from the same study. The amount of nitrogen contained in plasma AAs, levels of blood urea nitrogen (BUN) (p < 0.0001) and changes in BUN (p < 0.0001) were smaller after the Test product compared with the Reference product. These findings suggest that the production of urea in proportion to systemic AA availability was significantly smaller after the administration of the Test product compared with the Reference product and that the test product conferred the increased utilization of AAs for protein synthesis and reduced their oxidation and conversion to urea. In the clinical setting, it is possible that the effects of PT™ observed on the disposition of free AAs in this study may translate to health benefits in terms of physiological body composition and growth if used for the treatment of subjects with phenylketonuria (PKU). Further investigation in patients with PKU is warranted.

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Activated Charcoal in Tricyclic Antidepressant Poisoning

Human Toxicology ◽

10.1177/096032718800700402 ◽

1988 ◽

Vol 7 (4) ◽

pp. 307-310 ◽

Cited By ~ 19

Author(s):

B-Å. Hultén ◽

R. Adams ◽

R. Askenasi ◽

V. Dallos ◽

S. Dawling ◽

...

Keyword(s):

Single Dose ◽

Activated Charcoal ◽

Peak Plasma ◽

Randomized Study ◽

Plasma Concentrations ◽

Gastric Lavage ◽

Systemic Absorption ◽

Plasma Drug ◽

Drug Concentrations ◽

Significant Difference

Tricyclic antidepressants (TCA) bind to activated charcoal both in vitro and in vivo in healthy volunteers after a therapeutic dose of TCA. These findings provide a basis for the routine use of activated charcoal in TCA poisoning. The object of this study was to examine the effect of a single dose of 20 g of activated charcoal in overdose patients. Ninety-one patients from four centres with suspected TCA overdose were entered into a randomized study. Gastric lavage was performed on all patients. Thirty-four received 20 g of activated charcoal and 43 served as controls. Fourteen patients were excluded. Plasma drug concentrations were taken on admission and at 1, 2, 4, 8 and 24 h. The incidence of toxic symptoms was registered during 24 h. There was no significant difference in the area under the plasma drug concentration versus time curve, the peak plasma concentrations or plasma half-lives between the two groups. Toxic symptoms were more frequent in the non-treated groups although this difference was not statistically significant. In patients with TCA overdose initially treated with gastric lavage, a single dose of 20 g of activated charcoal had no effect on the systemic absorption or elimination of TCA.

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1283. New Generation Antiviral Conjugate (AVC): Stable, Safe, and Single

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1466 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S656-S657

Author(s):

Voon Ong ◽

James Levin ◽

Allen Borchardt ◽

Thomas P Brady ◽

Thanh Lam ◽

...

Keyword(s):

Single Dose ◽

Mouse Model ◽

Treatment Efficacy ◽

Influenza A ◽

Plasma Concentrations ◽

Clinical Signs ◽

Toxicology Study ◽

Prevention And Treatment ◽

Long Acting

Abstract Background CD377 is a novel antiviral Fc-conjugate (AVC) development candidate for influenza prevention and treatment, comprising multiple copies of a novel potent small-molecule antiviral and the Fc domain of human IgG1. CD377 was designed as a stable, long-acting molecule for treatment and prevention of influenza A and B. Studies were conducted to characterize CD377 stability/pharmacokinetics (PK), single-dose efficacy in influenza models, and safety/toxicology. Methods PK in the mouse (1-100 mg/kg), rat (5-50 mg/kg), ferret (3 mg/kg), and monkey (5-20 mg/kg) were studied by sampling plasma over a 1-2 week interval. Plasma levels of intact molecule and total Fc were measured by neuraminidase (NA)-capture and Fc-capture with Fc-detection ELISA, respectively. Two-week safety/toxicology (bodyweight, coagulation, clinical signs, chemistries, hematology, cytokines, urinalsis, histopathology) was evaluated in monkeys (5-20 mg/kg on days 1 and 8). Prophylaxis efficacy was studied in a lethal influenza mouse model using a single dose of CD377 (0.3–3 mg/kg) 28 days prior to intranasal (IN) challenge with 3x the LD95 of A/California/07/2009 (H1N1)pdm, A/Hong Kong/1/68 (H3N2), or B/Malaysia (Victoria lineage). Treatment efficacy was studied in a similar mouse model using a single dose of CD377 (0.3–3 mg/kg) administered 2 hours after IN challenge with A/CA/12/2012 (H1N1)pdm. Results Plasma concentrations measured by Fc-capture/Fc-detection and NA-capture/Fc-detection were comparable, indicating that CD377 remained intact in vivo. In species tested, CD377 t1/2 was 3–10 days. Dose proportional increases in exposure were observed, notably from 1–100 mg/kg in mouse. High bioavailability (77%) was observed after subcutaneous (SC) or intramuscular (IM) administration. A single SC dose of 1 mg/kg administered 28 days prior to infection provided 100% protection against H1N1, B, and H3N2 subtypes in mouse (Fig. 1). Treatment efficacy was observed with a single 0.3 mg/kg IM dose. The 2-week monkey toxicology study showed no adverse effects. Figure 1. Efficacy (Survival and Body Weight) of CD377 in a 28-Day Prevention Model Against Influenza H1N1, H3N2, and B Subtypes in Mouse (IN infection challenge on Day t=0 and CD377 dosed t–28 days). Conclusion The stability and safety of CD377, together with its long half-life and efficacy with a single dose, support the potential of CD377 as a long-acting, novel AVC for the prevention and treatment of influenza. Disclosures Voon Ong, PhD, Cidara Therapeutics, Inc. (Employee, Shareholder) James Levin, PhD, Cidara Therapeutics (Shareholder) Allen Borchardt, PhD, Cidara Therapeutics (Employee) Thomas P. Brady, PhD Chemistry, Cidara Therapeutics (Employee) Thanh Lam, PhD, Cidara Therapeutics (Shareholder) Alain Noncovich, PhD, Cidara Therapeutics (Shareholder) Joanne Fortier, BSc, Cidara Therapeutics (Employee, Shareholder) Karin Amundson, B.S., Cidara Therapeutics (Shareholder) Jeffrey B. Locke, PhD, Cidara Therapeutics, Inc. (Employee, Shareholder) Amanda Almaguer, Bachelors, Cidara Therapeutics, Inc. (Employee, Shareholder) Nicholas Dedeic, n/a, Cidara Therapeutics (Employee) Grayson Hough, MS - Chemistry, Cidara Therapeutics (Employee) Jason Cole, PhD, Cidara Therapeutics (Shareholder) Simon Döhrmann, PhD, Cidara Therapeutics (Shareholder) Rajvir Grewal, n/a, Cidara Therapeutics, Inc. (Employee, Shareholder) Elizabeth Abelovski, B.S., Cidara Therapeutics (Shareholder) James M. Balkovec, PhD, Cidara Therapeutics (Consultant, Shareholder) Ken Bartizal, PhD, Cidara Therapeutics, Inc. (Consultant, Shareholder) Les Tari, PhD, Cidara Therapeutics (Shareholder)

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Comparative Plasma Heparin Levels after Subcutaneous Sodium and Calcium Heparin

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648673 ◽

1978 ◽

Vol 40 (02) ◽

pp. 397-406 ◽

Cited By ~ 8

Author(s):

Joyce Low ◽

J C Biggs

Keyword(s):

Peak Plasma ◽

Plasma Concentrations ◽

Factor Xa ◽

Normal Subjects ◽

Sodium Salts ◽

Sodium Heparin ◽

Significant Difference ◽

Heparin Plasma ◽

Calcium Heparin ◽

Plasma Heparin

SummaryComparative plasma heparin levels were measured in normal subjects injected subcutaneously with 5,000 units of the sodium and calcium salts of heparin. Plasma heparin levels were measured up to 7 hr post-injection by an anti-factor Xa assay (Denson and Bonnar 1973). Preliminary studies indicated that heparin levels were reproducible in subjects who received two injections of the same heparin. Peak plasma concentrations (Cmax) and the time at which peak concentration was reached (Tmax) varied greatly from subject to subject. In one group of subjects (15) two commonly used heparins, a sodium heparin (Evans) and a calcium heparin (Choay) were compared. Peak heparin concentrations were not significantly different. However the Tmax for the sodium heparin (1.5 hr) was significantly earlier than the Tmax for the calcium heparin (3 hr) and this was not due to a difference in the volume of the two heparin injections. No significant difference could be detected in the plasma clearance rate and the molecular weight distribution of the two heparins.In two other groups of subjects, sodium and calcium preparations from two manufacturers were compared. In general, the sodium salts gave rise to significantly higher plasma concentrations, which could be interpreted as a greater bioavailability of sodium salts. These results indicate that the salt of the heparin can influence the plasma concentration achieved after subcutaneous injection.

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Bioavailability in Rats of Human Recombinant Tissue Plasminogen Activator After Subcutaneous and Intramuscular Injection

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661671 ◽

1986 ◽

Vol 56 (03) ◽

pp. 299-301 ◽

Cited By ~ 5

Author(s):

L J Garcia Frade ◽

S Poole ◽

S Hanley ◽

L J Creighton ◽

A D Curtis ◽

...

Keyword(s):

Plasminogen Activator ◽

Tissue Plasminogen Activator ◽

Fibrinolytic Activity ◽

Inferior Vena ◽

Peak Plasma ◽

Plasma Concentrations ◽

Vena Cava ◽

Recombinant Tissue Plasminogen Activator ◽

Fibrin Plate ◽

Tissue Plasminogen

SummaryThe bioavailability of human recombinant tissue plasminogen activator (rt-PA) in rats was measured after subcutaneous (s.c.) and intramuscular (i.m.) injection. Rt-PA was absorbed after both i.m. and s.c. injection, giving peak plasma concentrations within 30 min and 1 h, respectively, with detectable concentrations up to 6 h. These peak values of bioavailable t-PA were obtained in a functional fibrin plate assay of euglobulin precipitates and expressed as +88% and +243% (for s.c. and i.m. routes respectively) above basal rat fibrinolytic activity. Prior injection of rt-PA, s.c. or i.m., significantly reduced the weights of thrombi induced in the inferior vena cava after injection.

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INFLUENCE OF METYRAPONE ON PLASMA CONCENTRATIONS OF TESTOSTERONE AND ANDROSTENEDIONE IN MAN

Acta Endocrinologica ◽

10.1530/acta.0.0680576 ◽

1971 ◽

Vol 68 (3) ◽

pp. 576-584 ◽

Cited By ~ 5

Author(s):

K. O. Nilsson ◽

B. Hökfelt

Keyword(s):

Body Weight ◽

Male Patient ◽

Gradual Increase ◽

Plasma Concentrations ◽

Plasma Testosterone ◽

Testosterone Levels ◽

Basal Plasma ◽

Normal Males ◽

A Minor ◽

Secondary Hypogonadism

ABSTRACT Metyrapone was administered either orally, 750 mg every four h, in a total of six doses, or intravenously 30 mg per kg body weight as a four h infusion. In three males with normal endocrine functions, metyrapone given orally or intravenously induced a fall in plasma testosterone and an elevation of androstenedione within 2–8 h. When metyrapone was administered to a patient given dexamethasone to suppress endogenous ACTH production, the androstenedione levels did not alter whereas the testosterone levels showed a slight, transient decrease. In two normal females metyrapone administration was followed by a marked increase in plasma androstenedione whereas testosterone showed only a minor, gradual increase. In one male patient with Addison's disease the basal plasma testosterone was normal whereas the level of androstenedione was low. Following metyrapone intravenously, there was a slight suppression of plasma testosterone but no change in the androstenedione concentration. In one patient with primary hypogonadism, two with secondary hypogonadism and two with Klinefelter's syndrome the plasma testosterone was low under basal conditions and did not change following metyrapone. Basal plasma androstenedione was within the range for normal males and increased markedly following metyrapone in all the cases.

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