Peripheral Pharmacokinetics Research Articles

A Phase 1, First-in-human, Randomized, Double-blind, Placebo-controlled, Single and Multiple Ascending Intravenous Dose Study of a novel TREM2 agonist (VGL101) in Healthy Volunteers (HVs) (S14.004)

<h3>Objective:</h3> To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of VGL101 in healthy adult participants after both single- (SAD) and multiple-ascending dose (MAD) administration. <h3>Background:</h3> VGL101 is a fully human monoclonal antibody targeting TREM2, in development for the treatment of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a rare, progressive, debilitating neurodegenerative disorder. TREM2, a receptor expressed on microglia in the brain is critical to microglial function in health and in disease. The activation of TREM2 by VGL101 is expected to enhance microglia function and neural tissue repair mechanisms regulated by microglia thereby slowing disease progression in ALSP. <h3>Design/Methods:</h3> The Phase 1 study has enrolled 74 HVs in several cohorts at doses up to 40mg/kg SAD and 20mg/kg MAD or placebo. Safety was assessed by the incidence of adverse events (AEs), changes in vital signs, laboratory tests, ECGs, and clinical evaluations. VGL101 serum and CSF PK and the PD of CSF soluble TREM2 (a marker of microglia target engagement) were characterized across single and multiple doses. <h3>Results:</h3> VGL101 demonstrated a favorable safety and tolerability profile at studied doses. Adverse events were mild, did not require intervention and resolved spontaneously. To date, there are no reports of SAEs or clinically meaningful abnormalities in vital signs, laboratory parameters or ECGs. VGL101 demonstrated approximately dose proportional peripheral pharmacokinetics with half-life supporting monthly dosing and brain penetration typical of IgG1 monoclonal antibodies. Dose and time dependent reduction in sTREM2 levels in the CSF was observed demonstrating CNS target engagement for VGL101. <h3>Conclusions:</h3> VGL101 demonstrated a favorable safety, PK profile and confirmation of CNS target engagement in healthy volunteers. The Phase 1 data supports further clinical development of VGL101 in ALSP. <b>Disclosure:</b> Dr. Papapetropoulos has received personal compensation for serving as an employee of Vigil Neuroscience . Dr. Papapetropoulos has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Acadia. Dr. Papapetropoulos has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Ventus Therapeutics Inc. Dr. Papapetropoulos has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Adamas Pharmaceuticals. Dr. Papapetropoulos has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Lipocine Inc. Dr. Papapetropoulos has stock in Vigil Neuroscience. Dr. Papapetropoulos has stock in Adamas. Dr. Papapetropoulos has stock in Lipocine. Andreas Meier has received personal compensation for serving as an employee of Voyager Therapeutics. Andreas Meier has received personal compensation for serving as an employee of Biogen. Mr. O’Mara has received personal compensation for serving as an employee of VIgil Neuroscience, LLC. Mr. Marsh has received personal compensation for serving as an employee of Vigil Neuroscience, Inc.. Mr. Marsh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Vigil Neuroscience, Inc.. Dr. Neelon has received personal compensation for serving as an employee of BridgeBio. Dr. Neelon has received personal compensation for serving as an employee of Vigil NeuroScience. An immediate family member of Dr. Neelon has received personal compensation for serving as an employee of Crisper Therapeutics. An immediate family member of Dr. Neelon has received personal compensation for serving as an employee of Mana Therapeutics. Dr. Neelon has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for BridgeBio. Dr. Neelon has stock in BridgeBio. Dr. Neelon has stock in VigilNeuro Science. An immediate family member of Dr. Neelon has stock in Cripser Therapeutics. An immediate family member of Dr. Neelon has stock in Mana Therapeutics. Dr. Neelon has received intellectual property interests from a discovery or technology relating to health care. Dr. Rajagovindan has received personal compensation for serving as an employee of Biogen. Dr. Rajagovindan has received personal compensation for serving as an employee of Vigil. Dr. Rajagovindan has stock in Biogen. Dr. Rajagovindan has stock in Vigil . Dr. Thackaberry has received personal compensation for serving as an employee of Vigil Neuroscience. Dr. Thackaberry has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Samsara Biocapital. Dr. Thackaberry has stock in Vigil Neurosciences. Dr. Stiles has received personal compensation for serving as an employee of Vigil Neuroscience. Dr. Stiles has received personal compensation for serving as an employee of Vertex Pharmaceuticals.

Dissociation in Pharmacokinetic Attenuation Between Central Dopamine D2 Receptor Occupancy and Peripheral Blood Concentration of Antipsychotics: A Systematic Review.

The objective of this study was to examine the extent of possible dissociation in pharmacokinetic decay between central dopamine D₂ receptor occupancy with antipsychotics and their peripheral blood concentrations. MEDLINE and Embase were searched using the following keywords: (positron emission tomography OR PET OR single-photon emission computed tomography OR SPECT) AND (dopamine OR D2) AND (receptor* OR occupanc*) AND antipsychotic*, with a limitation of English language (last search: December 14, 2019). The search identified 18 studies that met the following criteria: (1) including patients with schizophrenia spectrum disorders and/or healthy subjects, (2) using positron emission tomography or single-photon emission computed tomography, and (3) examining the time courses of D₂ occupancy with antipsychotics and their blood concentrations. The ratios of D₂ occupancy reduction rate (%) from peak to blood concentration reduction rate (%) from peak (relative attenuation ratio) were calculated. Among the studies, oral risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, perospirone, haloperidol, sulpiride, and clozapine and long-acting injectable risperidone and haloperidol were included. Relative attenuation ratios were less than 1, indicating a slower central versus peripheral attenuation, across the time points for all antipsychotic types and doses with only a few exceptions. The ratio decreased in a dose-dependent as well as a peak D₂ occupancy-dependent fashion. It contrarily increased in a time-dependent manner. The findings indicate pharmacokinetic attenuation of antipsychotics was generally slower at the central versus the peripheral level and pose a critical challenge to the current dosing strategy that primarily relies on peripheral pharmacokinetics of antipsychotics.

Pharmacokinetics and anti-inflammatory effect of naproxen in rats with acute and subacute spinal cord injury.

Previous reports have warned about the influence of spinal cord injury (SCI) on the pharmacokinetics of various drugs. However, the role of SCI in the efficacy and safety of pharmacotherapy remains unknown. Thereby, our aim was to explore the role of SCI on pharmacokinetics and anti-inflammatory effect of naproxen in response to a local inflammatory challenge. Rats received a severe contusive SCI at T9 or sham injury. Pharmacokinetics of a single intravenous dose of naproxen (10 mg kg-1) was studied at days 1 and 15 post-surgery. For the anti-inflammatory assessment, carrageenan was subcutaneously injected in forelimb and hindlimb paws at the same post-surgery periods, and naproxen efficacy was evaluated measuring paw swelling. Plasma protein concentrations and body weight changes were also determined. Plasma naproxen levels and pharmacokinetic parameters were unchanged by acute injury, but subacute injury generated alterations in volume of distribution, clearance, and bioavailability, resulting in significantly reduced plasma naproxen concentrations, in the absence of changes in plasma proteins. Assessment of naproxen anti-inflammatory activity during the acute stage of injury could not be determined because of carrageenan failure to elicit swelling. During the subacute stage, naproxen anti-inflammatory effect on forelimbs (above injury) was similar to that observed in sham-injured animals, while it was almost absent in paralyzed hindlimbs. Under conditions of SCI and peripheral inflammation, pharmacokinetics and anti-inflammatory activity of naproxen vary according to post-injury timing and neurological status of the assessed region.

Hepatic Artery and Peripheral Vein Pharmacokinetics of Raltitrexed in Swine After the Administration of a Hepatic Arterial Infusion.

Hepatic Arterial Infusion (HAI) with raltitrexed has become an effective treatment for hepatocellular cancer and colorectal cancer liver metastases. However, traditional Body Surface Area (BSA)-based dosing is unsafe or ineffective, and a more accurate model-based approach is required. In this study, domestic swine were given 1 mg or 4 mg raltitrexed administered by an HAI with infusion times of 30, 60 and 120 min. Hepatic Artery (HA) and Peripheral Vein (PV) samples were collected, and a twocompartment model with an elimination pathway was established to describe the in vivo behavior of raltitrexed. The clearance was 0.27 L/min, and the volumes of distribution were 0.35 and 6.65 L for the HA and PV compartments, respectively. The goodness-of-fit plots and visual predictive checks suggested that the proposed pharmacokinetic model agreed well with the observations. The pharmacokinetic model could be helpful in quantitatively describing the detailed processes of raltitrexed activity administered by HAI and determining an appropriate dosing regimen for preclinical and clinical studies.

Abstract OT1-07-01: Phase 1/2 study of topical SOR007 (nanoparticle paclitaxel ointment) for cutaneous metastasis

Abstract Background: Cutaneous metastases are common in non-skin cancers, resulting in considerable morbidity, infection, pain, and negatively impacting quality of life. No standard of care exists for effective control of cutaneous metastases, which is a significant unmet need in oncology. Paclitaxel has shown effectiveness in the treatment of ovarian, breast, non-small cell lung, and pancreatic cancers and is approved by the United States Food and Drug Administration for the systemic treatment of many types of malignancies. We hypothesize that SOR007, or nanoparticulate paclitaxel ointment may be well tolerated and effective in the treatment of cutaneous metastases. Trial Design: This trial is a Phase 1/2, open-label study evaluating the safety, tolerability, and preliminary efficacy of three concentrations of SOR007 (0.15%, 1.0%, and 2.0%) ointment applied topically, twice daily, to non-melanoma cutaneous metastases during a 3+3 dose-ascending or dose expansion phase. Subjects will self-apply SOR007 ointment twice daily on Days 1 to 28, to a 50 cm2 area containing an eligible lesion. If a single dose limiting toxicity (DLT) is identified in the three subjects, an additional three subjects will be enrolled at the same dose level. If one or more DLT occur in the three additional subjects, dose escalation will stop and the prior dose level will be determined as the Maximum Tolerated Dose (MTD) and taken forward into the dose expansion phase. If no further DLT are identified, dose escalation will continue, until either a DLT is identified at a higher dose or the top dose of 2% is reached. Once DLT is determined, additional subjects will be enrolled in the expansion phase, to total up to 12 subjects at the top dose. Specific Aims: 1) The primary objective of this study is to determine preliminary safety and tolerability of topical SOR007. Secondary endpoints include: 2) evaluating preliminary efficacy based on RECIST criteria, photograph documentation of lesion size in longest diameter, and objective clinical response. 3) We will evaluate potential reduction in pain at the treatment area. 4) We will determine the peripheral blood pharmacokinetics of topical SOR007 applied to cutaneous metastases. Eligibility criteria: Male and female patients over the age of 18 with malignancies resulting in cutaneous metastasis originating from: breast, lung, head and neck, pancreatic, urinary bladder, prostate, testicular, ovarian, uterine, cervical, gastric, adrenal, thyroid, parathyroid cancers or other solid tumors which previously responded to taxane treatment are eligible to participate. Patients' last dose of any systemic non-taxane cytotoxic chemotherapy should be completed at least one day prior to the trial. Patients' last dose of any systemic taxane cytotoxic chemotherapy should be completed at least 4 weeks prior to the trial. Patients should be ECOG 0-2 with a minimum life expectancy of at least 3 months. Open or ulcerated wound(s) extending through the dermis are not eligible. Statistical methods: Data will be analyzed by descriptive statistics. Present accrual and target accrual: To date, we have enrolled 3 of a maximum of 24 subjects. Citation Format: Lang JE, Chawla S, Chang J, diZerega G, Cavanna-Mast RM, Savoie C, Lacouture M. Phase 1/2 study of topical SOR007 (nanoparticle paclitaxel ointment) for cutaneous metastasis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-07-01.

Pupillometry as an indicator of L-DOPA dosages in Parkinson's disease patients.

Dopamine was shown to induce mydriasis by excitation of alpha-adrenergic receptors at the dilator pupillae muscle. Pupilla diameter may thus serve as an indirect measure of peripheral pharmacokinetics of L-DOPA and dopamine. The aim of this study is to evaluate the effect of L-DOPA dosage on pupillometric parameters in Parkinson's disease (PD) patients. Sixteen PD patients and 14 healthy control subjects (CS) were studied. The statistical analysis revealed significant differences between CS and PD patients for the mean maximum and minimum pupil diameters (p=0.017, p=0.028, respectively), with higher values found in PD. Moreover, a significant dose-response relationship was found between the maximum pupil diameter and both the morning L-DOPA dose (R 2=0.78) and the total daily L-DOPA dose (R 2=0.93). A sigmoid-shaped curve best describes the dose-response relationship, with a ceiling effect at about 400mg L-DOPA daily dose. In conclusion, measuring pupillometric parameters represents a sensitive tool for non-invasive evaluation of the peripheral effect of L-DOPA, especially with daily doses below 400mg L-DOPA.

Dose-exposure-response relationship between AZD6738 and peripheral monocytes.

e14063 Background: AZD6738 is a potent, selective inhibitor of the ataxia telangiectasia and Rad3-related (ATR) serine/threonine-specific protein kinase with good selectivity against other phosphatidylinositol 3-kinase-related kinase (PIKK) family members. To support dose/schedule guidance through mathematical modelling of clinical pharmacokinetic/pharmacodynamic relationships, we sought to determine quantitative pharmacodynamic effects of AZD6738 in peripheral blood with respect to drug exposure. Methods: We assessed peripheral blood cell subpopulations in clinical studies of AZD6738 used either as a monotherapy, a combination with the PARP-1 inhibitor olaparib and in combination with the PD-L1 inhibitor durvalumab through both blood analyser and flow cytometry characterization. Peripheral pharmacokinetics of AZD6738 were also assessed. Results: Levels of peripheral monocytes were suppressed in a dose-dependent manner for the duration of AZD6738 dosing resulting in a decrease of up to 80% within the first 7 consecutive days of AZD6738 treatment; these results were consistent across studies. Upon cessation of an AZD6738 dosing interval monocyte levels return to baseline values within 14 days; in combination with durvalumab there is a trend for the rebound in monocyte counts to surpass baseline levels by up to 20%. Monocyte suppression is specific to AZD6738 and not found with either single agent olaparib or single agent durvalumab, possibly attributable to defective base excision repair in monocytes and lack of PARP-1. Monocytes were found to be the most sensitive cell type to AZD6738 treatment compared with neutrophils, platelets, haemoglobin or lymphocytes. Conclusions: This drug effect of AZD6738 is consistent with natural clearance of peripheral monocytes under suppression of monocyte precursor proliferation in the bone marrow, suggestive of a change in the equilibrium between production and elimination of peripheral monocytes. Used as a surrogate marker of target inhibition, a mathematical model of the AZD6738/monocyte dose-exposure-response relationship is described and has been used to inform AZD6738 Phase 2 dose and schedule.

Tau Proteins Cross the Blood-Brain Barrier.

Tauopathies are a hallmark of many neurodegenerative diseases, including Alzheimer's disease and traumatic brain injuries. It has been demonstrated that amyloid-beta peptides, alpha-synuclein, and prion proteins cross the blood-brain barrier (BBB), contributing to their abilities to induce disease. Very little is known about whether tau proteins can cross the BBB. Here we systematically characterized several key forms of tau proteins to cross the BBB, including Tau-441 (2N4R), Tau-410 (2N3R), truncated tau 151-391 (0N4R), and truncated tau 121-227. All of these tau proteins crossed the BBB readily and bidirectonally; however, only Tau-410 had a saturable component to its influx. The tau proteins also entered the blood after their injection into the brain, with Tau 121-227 having the slowest exit from brain. The tau proteins varied in regards to their enzymatic stability in brain and blood and in their peripheral pharmacokinetics. These results show that blood-borne tau proteins could contribute to brain tauopathies. The result also suggest that the CNS can contribute to blood levels of tau, raising the possibility that, as suggested for other misfolded proteins, blood levels of tau proteins could be used as a biomarker of CNS disease.

Pluronic modified leptin with increased systemic circulation, brain uptake and efficacy for treatment of obesity

Modification of hydrophilic proteins with amphiphilic block copolymers capable of crossing cell membranes is a new strategy to improve protein delivery to the brain. Leptin, a candidate for the treatment of epidemic obesity, has failed in part because of impairment in its transport across the blood–brain barrier (BBB) that develops with obesity. We posit that modification of leptin with poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide), Pluronic P85 (P85) might permit this protein to penetrate the BBB independently of its transporter, thereby overcoming peripheral leptin resistance. Here we report that peripherally administered leptin–P85 conjugates exhibit biological activity by reducing food intake in mouse models of obesity (ob/ob, and diet-induced obese mouse). We further generated two new leptin–P85 conjugates: one, Lep(ss)–P85(L), containing one P85 chain and another, Lep(ss)–P85(H), containing multiple P85 chains. We report data on their purification, analytical characterization, peripheral and brain pharmacokinetics (PK). Lep(ss)–P85(L) crosses the BBB using the leptin transporter, and exhibits improved peripheral PK along with increased accumulation in the brain compared to unmodified leptin. Lep(ss)–P85(H) also has improved peripheral PK but in a striking difference to the first conjugate penetrates the BBB independently of the leptin transporter via a non-saturable mechanism. The results demonstrate that leptin analogs can be developed through chemical modification of the native leptin with P85 to overcome leptin resistance at the level of the BBB, thus improving the potential for the treatment of obesity.

Poster #S250 PRESCRIPTION PATTERNS PRIOR TO CLOZAPINE INITIATION IN FIRST-EPISODE PSYCHOSIS

Background: Many antipsychotic drugs, including perphenazine, are routinely administered in a divided dosage regimen because of their relatively short plasma half-lives. Whether this is actually necessary has never been extensively investigated. The objective of this study was to evaluate the impact of once vs. twice daily dosing of perphenazine on clinical outcomes in patients with schizophrenia. Methods: Data from phase 1 of the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) were used. Patients with schizophrenia randomly allocated to treatment with perphenazine were also randomly assigned to once daily (N=133) or twice daily (N=124) dosing and followed over 18 months. These two groups were compared regarding the following outcomes: Effectiveness – discontinuation rate and time to discontinuation (primary outcomes): Efficacy – Positive and Negative Syndrome Scale, Clinical Global Impression – Severity scale, Calgary Depression Scale for Schizophrenia, and Drug Attitude Inventory; Safety/Tolerability – Abnormal Involuntary Movement Scale, Barnes Akathisia Rating Scale, Simpson-Angus Scale, body weight, treatment emergent adverse events, and concomitant psychotropic medications; Medication Adherence – Pill count and clinician rating scale. Results: No significant differences were found in any outcome measures between the once daily and twice daily dosing groups, which remained the same when using the average dose of perphenazine as a covariate. Discussion: The present findings indicate that despite a pharmacokinetic rationale supporting dosing of perphenazine at least twice daily, once daily dosing produces similar clinical outcomes. These findings also suggest it may be necessary to revisit the longstanding axiom that antipsychotic dosing be established based on peripheral pharmacokinetics.

11C-MK-8278 PET as a Tool for Pharmacodynamic Brain Occupancy of Histamine 3 Receptor Inverse Agonists

The histamine 3 (H3) receptor is a presynaptic autoreceptor in the central nervous system that regulates the synthesis and release of histamine and modulates the release of other major neurotransmitters. H3 receptor inverse agonists (IAs) may be efficacious in the treatment of various central nervous system disorders, including excessive daytime sleepiness, attention deficit hyperactivity disorder, Alzheimer disease, ethanol addiction, and obesity. Using PET and a novel high-affinity and selective radioligand (11)C-MK-8278, we studied the tracer biodistribution, quantification, and brain H3 receptor occupancy (RO) of MK-0249 and MK-3134, 2 potential IA drugs targeting cerebral H3 receptors, in 6 healthy male subjects (age, 19-40 y). The relationship among H3 IA dose, time on target, and peripheral pharmacokinetics was further investigated in 15 healthy male volunteers (age, 18-40 y) with up to 3 PET scans and 3 subjects per dose level. The mean effective dose for (11)C-MK-8278 was 5.4 ± 1.1 μSv/MBq. Human brain kinetics showed rapid high uptake and fast washout. Binding potential values can be assessed using the pons as a reference region, with a test-retest repeatability of 7%. Drug RO data showed low interindividual variability per dose (mean RO SD, 2.1%), and a targeted 90% RO can be reached for both IAs at clinically feasible doses. (11)C-MK-8278 is a useful novel PET radioligand for determination of human cerebral H3 receptor binding and allows highly reproducible in vivo brain occupancy of H3-targeting drugs, hereby enabling the evaluation of novel compounds in early development to select doses and schedules.

Brain and peripheral pharmacokinetics of levodopa in the cynomolgus monkey following administration of opicapone, a third generation nitrocatechol COMT inhibitor

ObjectiveThe present study aimed at evaluating the effect of opicapone, a third generation nitrocatechol catechol-O-methyltransferase (COMT) inhibitor, on the systemic and central bioavailability of 3,4-dihydroxy-l-phenylalanine (levodopa) and related metabolites in the cynomolgus monkey. MethodsFour monkeys, implanted with guiding cannulas for microdialysis probes, in the substantia nigra, dorsal striatum and prefrontal cortex, were randomized in two groups that received, in a crossover design, vehicle or 100 mg/kg opicapone for 14 days. Twenty-three hours after last administration of vehicle or opicapone, animals were challenged with levodopa/benserazide (12/3 mg/kg). Extracellular dialysate and blood samples were collected over 360 min (at 30 min intervals) for the assays of catecholamine and COMT activity. ResultsOpicapone increased levodopa systemic exposure by 2-fold not changing Cmax values and reduced both 3-O-methyldopa (3-OMD) exposure and Cmax values by 5-fold. These changes were accompanied by ∼76–84% reduction in erythrocyte COMT activity. In dorsal striatum and substantia nigra, opicapone increased levodopa exposure by 1.7- and 1.4-fold, respectively, reducing 3-OMD exposure by 5- and 7-fold respectively. DOPAC exposure was increased by 4-fold in the substantia nigra. In the prefrontal cortex, opicapone increased levodopa exposure and reduced 3-OMD levels by 2.3- and 2.4-fold, respectively. ConclusionsOpicapone behaved as long-acting COMT inhibitor that markedly increased systemic and central levodopa bioavailability. Opicapone is a strong candidate to fill the unmet need for COMT inhibitors that lead to more sustained levodopa levels in Parkinson's disease patients.

Effects of Hepatic Ischemia-Reperfusion Injury on the P-Glycoprotein Activity at the Liver Canalicular Membrane and Blood–Brain Barrier Determined by In Vivo Administration of Rhodamine 123 in Rats

To investigate the effects of normothermic hepatic ischemia-reperfusion (IR) injury on the activity of P-glycoprotein (P-gp) in the liver and at the blood-brain barrier (BBB) of rats using rhodamine 123 (RH-123) as an in vivo marker. Rats were subjected to 90min of partial ischemia or sham surgery, followed by 12 or 24h of reperfusion. Following intravenous injection, the concentrations of RH-123 in blood, bile, brain, and liver were used for pharmacokinetic calculations. The protein levels of P-gp and some other transporters in the liver and brain were also determined by Western blot analysis. P-gp protein levels at the liver canalicular membrane were increased by twofold after 24h of reperfusion. However, the biliary excretion of RH-123 was reduced in these rats by 26%, presumably due to IR-induced reductions in the liver uptake of the marker and hepatic ATP concentrations. At the BBB, a 24% overexpression of P-gp in the 24-h IR animals was associated with a 30% decrease in the apparent brain uptake clearance of RH-123. The pharmacokinetics or brain distribution of RH-123 was not affected by the 12-h IR injury. Hepatic IR injury may alter the peripheral pharmacokinetics and brain distribution of drugs that are transported by P-gp and possibly other transporters.

Effects of short-term portacaval anastomosis on the peripheral and brain disposition of the blood–brain barrier permeability marker sodium fluorescein in rats

Contradictory results have been reported with regard to the effects of various models of hepatic encephalopathy on the blood–brain barrier (BBB) permeability, which may be due partly to the use of brain concentrations of BBB markers without attention to their peripheral pharmacokinetics. The purpose of the current study was to investigate the effects of short-term portacaval anastomosis (PCA), a type B model of hepatic encephalopathy, on the peripheral pharmacokinetics and brain distribution of sodium fluorescein (FL), which is a small molecule marker of BBB passive permeability. A single 25mg/kg dose of FL was administered intravenously to 10-day PCA and sham-operated rats, and serial blood and bile (0–30min) and terminal (30min) brain samples were collected, and the concentrations of FL and its glucuronidated metabolite (FL-Glu) were measured by HPLC. Additionally, the free fractions of FL (fu) in all the plasma samples were determined, and the effects of bile salts on fu were investigated in vitro. Passive permeability of BBB to FL was estimated by brain uptake clearance (Kin) based on both the brain concentrations of FL and plasma concentrations of free (unbound) FL. PCA caused a 26% increase in the fu of FL in plasma, which was due to competition of bile acids with FL for binding to plasma proteins. Additionally, PCA reduced the biliary excretion of FL-Glu by 55%. However, free Kin values (µl/min/g brain) for the sham (0.265±0.034) and PCA (0.228±0.038) rats were not significantly different. It is concluded that whereas 10-day PCA alters the peripheral pharmacokinetics of FL, it does not significantly affect the BBB permeability to the marker.

Inhibiting the TLR4‐MyD88 signalling cascade by genetic or pharmacological strategies reduces acute alcohol‐induced sedation and motor impairment in mice

Emerging evidence implicates a role for toll-like receptor 4 (TLR4) in the CNS effects of alcohol. The aim of the current study was to determine whether TLR4-MyD88-dependent signalling is involved in the acute behavioural actions of alcohol and if alcohol can activate TLR4-downstream MAPK and NF-κB pathways. The TLR4 pathway was evaluated using the TLR4 antagonist (+)-naloxone (µ-opioid receptor-inactive isomer) and mice with null mutations in the TLR4 and MyD88 genes. Sedation and motor impairment induced by a single dose of alcohol were assessed by loss of righting reflex (LORR) and rotarod tests, separately. The phosphorylation of JNK, ERK and p38, and levels of IκBα were measured to determine the effects of acute alcohol exposure on MAPK and NF-κB signalling. After a single dose of alcohol, both pharmacological inhibition of TLR4 signalling with (+)-naloxone and genetic deficiency of TLR4 or MyD88 significantly (P < 0.0001) reduced the duration of LORR by 45-78% and significantly decreased motor impairment recovery time to 62-88% of controls. These behavioural actions were not due to changes in the peripheral or central alcohol pharmacokinetics. IκBα levels responded to alcohol by 30 min in mixed hippocampal cell samples, from wild-type mice, but not in cells from TLR4- or MyD88-deficient mice. These data provide new evidence that TLR4-MyD88 signalling is involved in the acute behavioural actions of alcohol in mice.

Pharmacokinetic evaluation of pramipexole

Introduction: Immediate-release (IR) pramipexole dihydrochloride is indicated for the treatment of signs and symptoms of idiopathic Parkinson's disease (PD). It is administered alone (without levodopa) or in combination with levodopa, during the entire progress of the disease, up to an advanced stage. Currently, it is also indicated for the treatment of moderate-to-severe primary restless legs syndrome (RLS). An extended-release (ER) formulation of pramipexole has been developed to allow a once-daily administration and to provide more stable dopaminergic stimulation in PD patients.Areas covered: This review summarizes the overall pharmacokinetic profile of pramipexole for both the IR and ER formulations. Also discussed are the clinically relevant determinants of pramipexole peripheral pharmacokinetics and the potential role of genetic and clinical determinants in drug efficacy.Expert opinion: Pramipexole is a non-ergot agonist with selective affinity for dopamine receptors of the D2 subfamily, in particular D3. Pramipexole has a very low affinity for serotoninergic 5-HT2A and 5-HT2B receptors, as well as D1-type receptors. Furthermore, it does not carry the risk to induce valvular heart disease or pulmonary and retroperitoneal fibrosis, seen with long-term use of the ergot-derived dopamine agonists. The recent introduction of a once-daily formulation poses significant advantages for patients, reflected by relatively stable plasma levels. The most obvious benefit is convenience of use and better adherence to treatment schedule. Additional advantages could include the opportunity to provide more continuous drug delivery in a fashion that could help minimize dyskinesia risk, if the drug is used early in the disease course.

Peripheral Pharmacokinetic Handling and Metabolism of L-Dopa in the Rat: The Effect of Route of Administration and Carbidopa Pretreatment

The effect of carbidopa (L-alpha-methyldopa hydrazine; 25 mg kg-1 i.p.) pretreatment on the pharmacokinetics and peripheral metabolism of orally and intra-aortically administered L-3,4-dihydroxyphenylalanine (L-dopa; 50 mg kg-1) has been examined in rats. Following intra-aortic (i.a.) administration, plasma levels of the drug declined biexponentially. Pretreatment with carbidopa resulted in higher plasma concentrations after i.a. administration of L-dopa, but had no effect on the half-life (t1/2) for its distribution or elimination. Oral L-dopa gave peak plasma concentrations at 1.5 h and then a log-linear decline between 1.5 and 6 h. Pretreatment with carbidopa also produced higher plasma concentrations of L-dopa given orally, and the t1/2 for its elimination tended to be increased compared with values achieved after the drug alone. Pretreatment with carbidopa decreased volume of distribution and total plasma clearance and increased area under the curve (0-infinity) after L-dopa i.a. and increased AUC0-infinity after L-dopa p.o. The fraction of the oral dose absorbed through the gut was not affected. Carbidopa pretreatment enhanced the accumulation of 3-O-methyldopa and decreased dopamine levels in plasma after both i.a. and oral administration of L-dopa. Higher plasma concentrations of 3,4-dihydroxyphenylacetic acid and homovanillic acid (HVA) were detected in the plasma after i.a. rather than oral administration of L-dopa and pretreatment with carbidopa greatly reduced these plasma concentrations. However, following oral L-dopa, only HVA levels were reduced by carbidopa pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of levodopa

This paper reviews the clinically relevant determinants of levodopa peripheral pharmacokinetics and main observed changes in the levodopa concentration-effect relationship with Parkinson's disease (PD) progression. Available clinically practical strategies to optimise levodopa pharmacokinetics and pharmacodynamics are briefly discussed. Levodopa shows particular pharmacokinetics including an extensive presystemic metabolism, overcome by the combined use of extracerebral inhibitors of the enzyme L: -amino acid decarboxylase and rapid absorption in the proximal small bowel by a saturable facilitated transport system shared with other large neutral amino acids. Drug transport from plasma to the brain is mediated by the same carriers operating in the intestinal mucosa. The main strategies to assure reproducibility of both intestinal absorption and delivery to the brain, and the clinical effect include standardization of levodopa dosing with respect to meal times and a controlled dietary protein intake. Levodopa plasma half-life is very short, resulting in marked plasma drug concentration fluctuations which are matched, as the disease progresses, to swings in the therapeutic response ("wearing-off" phenomena). "Wearing-off" phenomena can also be associated, at the more advanced disease stages, with a "negative", both parkinsonism-exacerbating and dyskinetic effect of levodopa at low, subtherapeutic plasma concentrations. Dyskinesias may also be related to high-levodopa, excessive plasma concentrations. Recognition of the different levodopa toxic response patterns can be difficult on a clinical basis alone and simultaneous monitoring of the levodopa concentration-effect relationship may prove useful to disclose the underlying mechanism and in planning the correct management. Clinically practical strategies to optimise levodopa pharmacokinetics, and possibly its therapeutic response, include liquid drug solutions, controlled release formulations and the use of inhibitors of levodopa metabolism. Unfortunately, these attempts have proved so far only partly successful, due to the complex alterations in cerebral levodopa kinetics which accompany the progressive degeneration of the nigrostriatal dopaminergic system in PD patients.

The role of the long-duration response to levodopa in Parkinson’s disease

The long-duration response (LDR) to levodopa is an important component of the therapeutic response to the drug in Parkinson's disease (PD). Some characteristics are peculiar: it is independent from peripheral pharmacokinetics of levodopa, but it is dependent on the intervals between doses and on the size of each dose. Once the LDR fully develops, it is stable and maximal. After stopping treatment, the decay rate is inversely related to the severity of PD; when the LDR decreases over time, the patients present a fluctuating motor response. Therapeutic strategies based on the development and maintenance of the LDR should be sought to maximize the clinical benefit induced by levodopa and to avoid the appearance of motor complications.

Pharmacokinetic-Pharmacodynamic Modeling of Levodopa in Patients With Advanced Parkinson Disease

The aims of the present study were to investigate the pharmacokinetic and pharmacodynamic (pk/pd) relationship of levodopa (l-dopa) in patients with advanced Parkinson disease (PD) and also to evaluate the effect of tolcapone on the pk/pd analysis of l-dopa in 1 patient with severe dyskinesias and fluctuations. The pharmacokinetics (plasma concentrations of l-dopa and 3-O-methyldopa [3-OMD]) and motor effects (global score of the Unified Parkinson's Disease Rating Scale-III) of a single dose of l-dopa (plus the peripheral decarboxylase inhibitor 1:4) were determined in 14 patients with advanced PD. Patients were classified into 2 groups according to Hoehn and Yahr scale (stages 2 and 3). In 1 patient with severe dyskinesias and fluctuations, pk/pd of l-dopa were evaluated before and after coadministration of tolcapone at 100 mg 2 times daily for 1 month. The pk/pd analysis was based on an estimate of the maximal response model with a semiparametric approach to effect site equilibrium. The highest levels of l-dopa and 3-OMD were observed in patients with stage 3 of Hoehn and Yahr scale. We showed differences in the pk/pd parameters after coadministration of tolcapone in 1 patient as well as the clinical improvement.Univariate analysis showed some significant correlations (P < 0.05) between l-dopa pk/pd parameters and patients' age, duration of l-dopa treatment, and duration of the disease. Multivariate analysis adjusted for patients' age, sex, duration of the disease, and Hoehn and Yahr stage showed that presence of diphasic (dyskinesia-improvement-dyskinesia [DID]) dyskinesias was the only independent predictor of larger threshold level - EC50 (mean concentration at half maximal effect) of l-dopa (P = 0.034). The motor complications during long treatment therapy in patients with advanced PD especially with stage 3 Hoehn and Yahr scale were correlated to the higher plasma concentrations of l-dopa. In the presented study, patients with motor complications, especially with DID dyskinesias, exhibited a larger threshold level (EC50). The clinical improvement of a patient who received l-dopa and tolcapone can be explained by tolcapone-induced changes of peripheral and central l-dopa pharmacokinetics, which led to a decrease of l-dopa EC50 and 3-OMD concentrations. Our data indicate that pk/pd analysis may be helpful for monitoring the efficiency of therapeutic strategy applied in PD patients.