The Effect of Inflammatory Bowel Disease and Irritable Bowel Syndrome on Pravastatin Oral Bioavailability: In vivo and in silico evaluation using bottom-up wbPBPK modeling.

The common disorders irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) can modify the drugs' pharmacokinetics via their induced pathophysiological changes. This work aimed to investigate the impact of these two diseases on pravastatin oral bioavailability. Rat models for IBS and IBD were used to experimentally test the effects of IBS and IBD on pravastatin pharmacokinetics. Then, the observations made in rats were extrapolated to humans using a mechanistic whole-body physiologically-based pharmacokinetic (wbPBPK) model. The rat in vivo studies done herein showed that IBS and IBD decreased serum albumin (> 11% for both), decreased PRV binding in plasma, and increased pravastatin absolute oral bioavailability (0.17 and 0.53 compared to 0.01) which increased plasma, muscle, and liver exposure. However, the wbPBPK model predicted muscle concentration was much lower than the pravastatin toxicity thresholds for myotoxicity and rhabdomyolysis. Overall, IBS and IBD can significantly increase pravastatin oral bioavailability which can be due to a combination of increased pravastatin intestinal permeability and decreased pravastatin gastric degradation resulting in higher exposure. This is the first study in the literature investigating the effects of IBS and IBD on pravastatin pharmacokinetics. The high interpatient variability in pravastatin concentrations as induced by IBD and IBS can be reduced by oral administration of pravastatin using enteric-coated tablets. Such disease (IBS and IBD)-drug interaction can have more drastic consequences for narrow therapeutic index drugs prone to gastric degradation, especially for drugs with low intestinal permeability.

Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis.

BACKGROUND: Hereditary angioedema with C1 inhibitor deficiency is characterized by recurrent, unpredictable swelling episodes caused by uncontrolled plasma kallikrein generation and excessive bradykinin release resulting from cleavage of high-molecular-weight kininogen. Lanadelumab (DX-2930) is a new kallikrein inhibitor with the potential for prophylactic treatment of hereditary angioedema with C1 inhibitor deficiency. METHODS: We conducted a phase 1b, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial. Patients with hereditary angioedema with C1 inhibitor deficiency were randomly assigned in a 2:1 ratio to receive either lanadelumab (24 patients) or placebo (13 patients), in two administrations 14 days apart. Patients assigned to lanadelumab were enrolled in sequential dose groups: total dose of 30 mg (4 patients), 100 mg (4 patients), 300 mg (5 patients), or 400 mg (11 patients). The pharmacodynamic profile of lanadelumab was assessed by measurement of plasma levels of cleaved high-molecular-weight kininogen, and efficacy was assessed by the rate of attacks of angioedema during a prespecified period (day 8 to day 50) in the 300-mg and 400-mg groups as compared with the placebo group. RESULTS: No discontinuations occurred because of adverse events, serious adverse events, or deaths in patients who received lanadelumab. The most common adverse events that emerged during treatment were attacks of angioedema, injection-site pain, and headache. Dose-proportional increases in serum concentrations of lanadelumab were observed; the mean elimination half-life was approximately 2 weeks. Lanadelumab at a dose of 300 mg or 400 mg reduced cleavage of high-molecular-weight kininogen in plasma from patients with hereditary angioedema with C1 inhibitor deficiency to levels approaching that from patients without the disorder. From day 8 to day 50, the 300-mg and 400-mg groups had 100% and 88% fewer attacks, respectively, than the placebo group. All patients in the 300-mg group and 82% (9 of 11) in the 400-mg group were attack-free, as compared with 27% (3 of 11) in the placebo group. CONCLUSIONS: In this small trial, administration of lanadelumab to patients with hereditary angioedema with C1 inhibitor deficiency reduced cleavage of high-molecular-weight kininogen and attacks of angioedema. (Funded by Dyax; ClinicalTrials.gov number, NCT02093923 .).

The development of a population physiologically based pharmacokinetic model for mycophenolic mofetil and mycophenolic acid in humans using data from plasma, saliva, and kidney tissue.

BACKGROUND: Mycophenolic acid (MPA) is used widely to prevent graft rejection in kidney-transplant patients. Therapeutic drug monitoring (TDM) in plasma requires an invasive procedure that is inconvenient, especially in pediatric patients. TDM in saliva is a more convenient non-invasive alternative compared with plasma. METHODS: A population physiologically based pharmacokinetic (Pop-PBPK) model of mycophenolate mofetil (MMF) and MPA with enterohepatic recycling was built and verified using previously published plasma, saliva, and kidney biopsy data in healthy and kidney-transplant adult patients. The verified model was then used to predict experimentally observed plasma and saliva MMF and MPA TDM data in Jordanian pediatric kidney transplant patients measured using LC-MS/MS. A correlation was established between plasma and saliva exposures in pediatrics. RESULTS: The developed LCMS was sensitive to both MMF and MPA in plasma and saliva. The developed Pop-PBPK model predicted well the previously reported MMF and MPA levels in plasma, saliva, and kidney tissue and those observed in the current study (more than 75% of observed data points were within 90% predictive interval of population simulations). A statistically significant correlation was found between plasma and saliva exposures for both MMF (Pop-PBPK predicted and observed) and MPA (Pop-PBPK predicted). CONCLUSION: Both MPA and MMF can be classified as class III compounds in the Salivary Excretion Classification System. Saliva is an alternative body fluid to plasma that can be used for TDM of MPA and MMF in kidney-transplant patients in pediatrics. Exposure to MPA and MMF in plasma, saliva, and kidney tissue was reliably predicted using the developed Pop-PBPK model.

Therapeutic Drug Monitoring of Vancomycin in Jordanian Patients. Development of Physiologically-Based Pharmacokinetic (PBPK) Model and Validation of Class II Drugs of Salivary Excretion Classification System (SECS).

Vancomycin is a commonly used antibiotic for multi-drug resistant gram-positive infections treatment, especially methicillin-resistant Staphylococcus aureus (MRSA). Despite that, it has wide individual pharmacokinetic variability and nephrotoxic effect. Vancomycin trough concentrations for 57 Jordanian patients were measured in plasma and saliva through immunoassay and liquid chromatography-mass spectrometry (LC-MS/MS), respectively. Plasma levels were within accepted normal range, with exception of 6 patients who showed trough levels of more than 20 µg/ml and vancomycin was discontinued. Bayesian dose-optimizing software was used for patient-specific pharmacokinetics prediction and AUC/MIC calculation. Physiological-based pharmacokinetic (PBPK) vancomycin model was built and validated through GastroPlus™ 9.8 using in-house plasma data. A weak correlation coefficient of 0.2478 (P=0.1049) was found between plasma and saliva concentrations. The suggested normal saliva trough range of vancomycin is 0.01906 to 0.028589 (µg/ml). Analysis of variance showed significant statistical effects of creatinine clearance and albumin concentration on dose-normalized Cmin plasma and saliva levels respectively, which is in agreement with PBPKmodeling. It can be concluded that saliva is not a suitable matrix for TDM of vancomycin. Trough levels in plasma matrix should always be monitored for the safety of patients.

Saliva versus Plasma Therapeutic Drug Monitoring of Gentamicin in Jordanian Preterm Infants. Development of a Physiologically-Based Pharmacokinetic (PBPK) Model and Validation of Class II Drugs of Salivary Excretion Classification System.

Gentamicin has proven to be a very successful treatment for bacterial infection, but it also can cause adverse effects, especially ototoxicity, which is irreversible. Therapeutic drug monitoring (TDM) in saliva is a more convenient non-invasive alternative compared to plasma. A physiologically-based pharmacokinetic (PBPK) model of gentamicin was built and validated using previously-published plasma and saliva data. The validated model was then used to predict experimentally-observed plasma and saliva gentamicin TDM data in Jordanian pediatric preterm infant patients measured using sensitive LCMS/MS method. A correlation was established between plasma and saliva exposures. The developed PBPK model predicted previously reported gentamicin levels in plasma, saliva and those observed in the current study. A good correlation was found between plasma and saliva exposures. The PBPK model predicted that gentamicin in saliva is 5-7 times that in plasma, which is in agreement with observed results. Saliva can be used as an alternative for TDM of gentamicin in preterm infant patients. Exposure to gentamicin in plasma and saliva can reliably be predicted using the developed PBPK model in patients.

An Open-Label, Randomized, Single-Dose, Crossover, Comparative Pharmacokinetics Study of YLB113 and the Etanercept Reference Product in Healthy Adult Male Subjects.

BACKGROUND AND OBJECTIVES: YLB113 is being developed as a biosimilar of the antitumor necrosis factor-alpha antagonist etanercept, which is approved for the treatment of moderate-to-severe rheumatoid arthritis (RA) and other chronic immune-mediated inflammatory diseases. An open-label, crossover, pharmacokinetic study was conducted to compare the relative bioavailability and safety of YLB113 and the etanercept reference product (RP) Enbrel®. METHODS: Healthy male subjects aged 18-50 years were randomized to receive a single subcutaneous dose of YLB113 in one period and the etanercept RP in another period. A washout period of 28 days separated the two treatment periods. Blood samples were collected for pharmacokinetic analysis predose and until 480 h postdose during both periods. RESULTS: Overall, 52 subjects were enrolled, including 51 subjects who completed the first period and 43 subjects who completed the second period. The 90% confidence intervals for the least squares means derived from an analysis of the log-transformed pharmacokinetic parameters maximum serum concentration (Cmax), area under the serum concentration-time curve (AUC) from 0 to the last measurable concentration (AUC(0-t)) and AUC from 0 to infinity (AUC(0-∞)) for etanercept were between the limits of 80 and 125%. Thus, YLB113 met the bioequivalence criterion. YLB113 and the etanercept RP were well tolerated, with 24 subjects reporting 53 adverse events, including 42 mild and 11 moderate events. Treatment-emergent adverse events were reported by 14 and 16 subjects following the administration of YLB113 and the etanercept RP, respectively. CONCLUSIONS: A single dose of YLB113 exhibited pharmacokinetic and safety profiles comparable with those of the etanercept RP in healthy adult male subjects. Therefore, YLB113 and the etanercept RP can be considered bioequivalent. These findings support the continued development of YLB113 for use in patients with RA. JORDAN FOOD & DRUG ADMINISTRATION UNIQUE TRIAL NUMBER: 31/Clinical/2018.

Effect of Flying at High Altitude on Early Exposure of Paracetamol in Humans.

Pharmacokinetics of paracetamol (APAP) was studied on-board during an air flight and compared to those on ground after 500 mg oral dose in 20 healthy human volunteer in parallel design study. Saliva samples were obtained every 15 min up to 2 h after dosing. Pharmacokinetic parameters were calculated by non compartmental analysis and one compartment models using Winnonlin program V5.2. Results have showed that on-board to ground ratios for area under curves AUC0→1, AUC0→2, time to reach maximum saliva concentration Tmax, absorption rate constant Ka and maximum saliva concentration Cmax were 0.62, 0.38, 1.01, 0.81 and 0.79 respectively. Effective membrane permeability coefficients were optimized by Nelder-Mead algorithm using Simcyp program V13. This showed similar rate of absorption and early exposure up to one hour, and lower bioavailability after 1 h on-board. This can be explained by the increased liver blood flow at high altitude that led to increased liver metabolism on-board. However, APAP elimination parameters were not calculated due to short sampling time. This suggests a need for dose adjustment on-board during long air flights, especially for narrow therapeutic index drugs with flow limited metabolism.

Saliva versus Plasma Therapeutic Drug Monitoring of Pregabalin in Jordanian Patients.

The objective is using saliva instead of plasma for pregabalin therapeutic drug monitoring (TDM) since saliva reflects the free non-protein bound drug concentration, simple and noninvasive sampling, cheaper and does not require the expertise of drawing blood. Forty four patients participated in this study, two samples of saliva and another two of blood were taken from each patient; first sample of both saliva and blood is the trough sample and was taken just before the first dose of the day and second sample is the peak sample and was taken 1 h after taking the first dose of the day. Descriptive statistics and t-testing after log transformation were done using Excel, p-value=0.05 was adopted for significant difference. Optimized effective intestinal permeability of pregabalin was estimated by PK-Sim program version 7. This study for the first time revealed that pregabalin is excreted in saliva and classified as class 1 based on Salivary Excretion Classification System (SECS). A good correlation of 0.71-0.83 between Cmin and Cmax of plasma and saliva pregabalin was observed respectively which indicate that saliva sampling is a good alternative matrix for pregabalin TDM. C/D-ratios were calculated to demonstrate pharmacokinetic variability of Pregabalin; the results showed that C/D-ratio was higher in women, elderly and in those patients who had Scr.≥0.9 mg/dl. Proposed pregabalin therapeutic ranges are 0.7 to 1.84 µg/ml in plasma and 0.055 to 0.145 µg/ml in saliva, for neuropathic pain, diabetic neuropathy and disc prolapse patients.

Bioequivalence evaluation of two brands of amoxicillin/clavulanic acid 250/125 mg combination tablets in healthy human volunteers: use of replicate design approach.

The purpose of this study was to apply a replicate design approach to a bioequivalence study of amoxicillin/clavulanic acid combination following a 250/125 mg oral dose to 23 subjects, and to compare the analysis of individual bioequivalence with average bioequivalence. This was conducted as a 2-treatment 2-sequence 4-period crossover study. Average bioequivalence was shown, while the results from the individual bioequivalence approach had no success in showing bioequivalence. In conclusion, the individual bioequivalence approach is a strong statistical tool to test for intra-subject variances and also subject-by-formulation interaction variance compared with the average bioequivalence approach.