The Laboratory Characterization of Fugitive Aerosol Emissions From a Standard Jet Nebulizer With and Without a Filtered Mouthpiece.

Background and objective The risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission from patients with coronavirus disease 2019 (COVID-19) during nebulization is unclear. In this study, we aimed to address this issue. Methods Fugitive emissions of aerosolized saline during nebulization were observed using a standard jet nebulizer fitted with unfiltered and filtered mouthpieces connected via a mannequin to a breathing simulator. Fugitive emissions were observed by using a laser sheet and captured on high-definition video, and they were measured by using optical particle counters positioned where a potential caregiver may be administering nebulization and three other locations in the sagittal plane at various distances downstream of the mannequin. Results The use of a standard unfiltered mouthpiece resulted in significant emission of fugitive aerosols ahead of and above the mannequin (spread over 2 m in front). A mouthpiece with a filter-adaptor effectively suppressed the emissions, with only minor leakage from the nebulizer cup. Particle count measurements supported the visual observations, providing total particle count levels and aerosol concentration levels at the measurement locations. The levels decayed slowly with downstream distance. Conclusions The visualization described above captured the dispersion of emitted aerosols in the plane of the laser sheet, aligned with the sagittal plane. The particle count measurements provided temporal and spatial distributions of the aerosol concentration levels over the time and locations considered. However, the exhaled air and aerosolized droplets spread three-dimensionally in front of and above the mannequin. The results visually highlight the effectiveness of using a filtered mouthpiece in suppressing the fugitive aerosols and identify an approach for limiting the occupational exposure of healthcare workers to these emissions while administering nebulized therapies.

ECG Evaluation as Part of the Clinical Pharmacology Strategy in the Development of New Drugs: A Review of Current Practices and Opportunities Based on Five Case Studies.

The International Conference on Harmonization (ICH) E14 document was revised in 2015 to allow concentration-corrected QT interval (C-QTc) analysis to be applied to data from early clinical pharmacology studies to exclude a small drug-induced effect on QTc. Provided sufficiently high concentrations of the drug are obtained in the first-in-human (FIH) study, this approach can be used to obviate the need for a designated thorough QT (TQT) study. The E14 revision has resulted in a steady reduction in the number of TQT studies and an increased use of FIH studies to evaluate electrocardiogram (ECG) effects of drugs in development. In this review, five examples from different sponsors are shared in which C-QTc analysis was performed on data from FIH studies. Case 1 illustrates a clearly negative C-QTc evaluation, despite observations of QTc prolongation at high concentrations in nonclinical studies. In case 2 C-QTc analysis of FIH data was performed prior to full pharmacokinetic characterization in patients, and the role of nonclinical assays in an integrated risk assessment is discussed. Case 3 illustrates a positive clinical C-QTc relationship, despite negative nonclinical assays. Case 4 demonstrates a strategy for characterizing the C-QTc relationship for a nonracemic therapy and formulation optimization, and case 5 highlights an approach to perform a preliminary C-QTc analysis early in development and postpone the definitive analysis until proof of efficacy is demonstrated. The strategy of collecting and storing ECG data from FIH studies to enable an informed decision on whether and when to apply C-QTc analysis to obviate the need for a TQT study is described.

Lung-restricted ALK5 inhibition avoids systemic toxicities associated with TGFß pathway inhibition.

Systemic therapies targeting transforming growth factor beta (TGFß) or TGFßR1 kinase (ALK5) have been plagued by toxicities including cardiac valvulopathy and bone physeal dysplasia in animals, posing a significant challenge for clinical development in pulmonary indications. The current work aims to demonstrate that systemic ALK5-associated toxicities can be mitigated through localized lung delivery. Lung-selective (THRX-144644) and systemically bioavailable (galunisertib) ALK5 inhibitors were compared to determine whether lung selectivity is sufficient to maintain local tissue concentrations while mitigating systemic exposure and consequent pathway-related findings. Both molecules demonstrated potent ALK5 activity in rat precision cut lung slices (PCLS; p-SMAD3 half-maximal inhibitory concentration [IC50], 141 nM and 1070 nM for THRX-144644 and galunisertib, respectively). In 14-day repeat-dose studies in rats, dose-related cardiac valvulopathy was recapitulated with oral galunisertib at doses ≥150 mg/kg/day. In contrast, inhaled nebulized THRX-144644 did not cause similar systemic findings up to the maximally tolerated doses in rats or dogs (10 and 1.5 mg/kg/day, respectively). THRX-144644 lung-to-plasma ratios ranged from 100- to 1200-fold in rats and dogs across dose levels. THRX-144644 lung trough (24 h) concentrations in rats and dogs ranged from 3- to 17-fold above the PCLS IC50 across tolerated doses. At a dose level exceeding tolerability (60 mg/kg/day; 76-fold above PCLS IC50) minimal heart and bone changes were observed when systemic drug concentrations reached pharmacologic levels. In conclusion, the current preclinical work demonstrates that localized pulmonary delivery of an ALK5 inhibitor leads to favorable TGFß pathway pharmacodynamic inhibition in lung while minimizing key systemic toxicities.

A Rare Case of Systemic Sarcoidosis in a Middle-Aged Female with a Solitary Thyroid Nodule.

Sarcoidosis is a multisystem inflammatory disease characterized by the presence of noncaseating granulomas. Sarcoidosis can affect any organ of the body, the lung being the most affected. Sarcoidosis rarely affects the thyroid gland, and only a few cases of thyroid-related sarcoidosis have been reported in the literature. Herein, we report a case of systemic sarcoidosis with multiple organ involvement in a patient with a solitary left thyroid nodule and benign Fine Needle Aspiration (FNA) findings. The patient was eventually diagnosed with thyroid sarcoidosis using a core needle biopsy of the thyroid nodule. With this case report, we highlight the limitations of the FNA. This case report has the objective to encourage clinicians to include thyroid sarcoidosis in the differential diagnosis of thyroid nodules in patients with systemic sarcoidosis even with unremarkable FNA findings.

Phase I study in healthy participants to evaluate safety, tolerability, and pharmacokinetics of inhaled nezulcitinib, a potential treatment for COVID-19.

Nezulcitinib (TD-0903), a lung-selective pan-Janus-associated kinase (JAK) inhibitor designed for inhaled delivery, is under development for treatment of acute lung injury associated with coronavirus disease 2019 (COVID-19). This two-part, double-blind, randomized, placebo-controlled, single ascending dose (part A) and multiple ascending dose (part B) phase I study evaluated the safety, tolerability, and pharmacokinetics (PK) of nezulcitinib in healthy participants. Part A included three cohorts randomized 6:2 to receive a single inhaled dose of nezulcitinib (1, 3, or 10 mg) or matching placebo. Part B included three cohorts randomized 8:2 to receive inhaled nezulcitinib (1, 3, or 10 mg) or matching placebo for 7 days. The primary outcome was nezulcitinib safety and tolerability assessed from treatment-emergent adverse events (TEAEs). The secondary outcome was nezulcitinib PK. All participants completed the study. All TEAEs were mild or moderate in severity, and none led to treatment discontinuation. Overall (area under the plasma concentration-time curve) and peak (maximal plasma concentration) plasma exposures of nezulcitinib were low and increased in a dose-proportional manner from 1 to 10 mg in both parts, with no suggestion of clinically meaningful drug accumulation. Maximal plasma exposures were below levels expected to result in systemic target engagement, consistent with a lung-selective profile. No reductions in natural killer cell counts were observed, consistent with the lack of a systemic pharmacological effect and the observed PK. In summary, single and multiple doses of inhaled nezulcitinib at 1, 3, and 10 mg were well-tolerated in healthy participants, with dose-proportional PK supporting once-daily administration.

Pharmacokinetics and pharmacodynamics of ampreloxetine, a novel, selective norepinephrine reuptake inhibitor, in symptomatic neurogenic orthostatic hypotension.

PURPOSE: Ampreloxetine is a novel, selective, long-acting norepinephrine reuptake (NET) inhibitor being investigated as a once-daily oral treatment for symptomatic neurogenic orthostatic hypotension (nOH) in patients with autonomic synucleinopathies. The purpose of this study was to characterize the pharmacokinetic and pharmacodynamic profiles of ampreloxetine in this target population. METHODS: Patients with nOH were enrolled in a multicenter, phase II clinical trial of ampreloxetine (NCT02705755). They received escalating doses over 5 days in the clinical research unit, followed by 20 weeks of open-label treatment and then a 4-week withdrawal. As neurochemical biomarkers of NET inhibition, we assayed plasma concentrations of norepinephrine (NE) and its main intraneuronal metabolite 3,4-dihydroxyphenylglycol (DHPG) pre- and post-ampreloxetine. RESULTS: Thirty-four patients with nOH were enrolled. Plasma ampreloxetine concentrations increased with repeated escalating doses, with peak concentrations observed 6-9 h post-drug administration. The median ampreloxetine dose in the 20-week treatment phase was 10 mg once daily. Plasma ampreloxetine concentrations reached steady state by 2 weeks, with stable plasma levels over 24 h. No influence of age or renal function on ampreloxetine plasma concentrations was observed. On treatment, compared to baseline, plasma NE significantly increased by 71% (p < 0.005), plasma DHPG significantly declined by 22% (p < 0.05), and the NE:DHPG ratio significantly increased (p < 0.001). CONCLUSIONS: Persistent elevation of plasma NE levels accompanied by reduced DHPG levels after ampreloxetine suggests reduced neuronal reuptake and metabolism of NE in postganglionic efferent sympathetic neurons. The findings are consistent with long-lasting NET inhibition, which may increase vasoconstrictor tone, supporting once-daily ampreloxetine dosing in patients with nOH.

Pharmacokinetics of Ampreloxetine, a Norepinephrine Reuptake Inhibitor, in Healthy Subjects and Adults with Attention-Deficit/Hyperactive Disorder or Fibromyalgia Pain.

BACKGROUND AND OBJECTIVE: Ampreloxetine is a novel norepinephrine reuptake inhibitor in development for the treatment of symptomatic neurogenic orthostatic hypotension. The objectives of this analysis were to define the pharmacokinetics of once-daily oral ampreloxetine and provide dose recommendations for clinical development. METHODS: We fitted a population pharmacokinetic model to ampreloxetine plasma concentrations from single- and multiple-ascending dose trials in healthy subjects and two phase II studies in adult subjects with attention-deficit/hyperactive disorder or fibromyalgia at doses of 2-50 mg. RESULTS: Ampreloxetine pharmacokinetics was best described by a two-compartment model with first-order absorption and elimination. The terminal half-life was 30-40 h, resulting in sustained drug concentrations for the entire 24-h dosing interval at steady state. Covariates of age, weight, or renal impairment did not impact ampreloxetine exposure. Cytochrome P450 2D6 phenotype had no influence on ampreloxetine exposure. Sex and smoking status were identified as statistically significant covariates, suggesting a role for cytochrome P450 1A2 in the elimination of ampreloxetine. Despite statistical significance, differences in ampreloxetine exposure in male vs female subjects and smokers vs non-smokers were not clinically meaningful at the recommended dose. At the 10-mg dose, > 75% norepinephrine transporter inhibition and < 50% serotonin transporter inhibition are anticipated for adult subjects. CONCLUSIONS: The population pharmacokinetic model effectively described the plasma concentration-time profile of ampreloxetine after single and multiple doses. Population pharmacokinetic/pharmacodynamic analysis justified using a fixed dosing regimen with no dose adjustments across a broad population and can be used to inform dosing strategies in future clinical studies. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier numbers NCT01693692 (fibromyalgia); NCT01458340 (attention-deficit/hyperactive disorder).

Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease.

BACKGROUND AND OBJECTIVES: Revefenacin is a lung-selective, long-acting muscarinic antagonist indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease. The objectives of this analysis were to evaluate the pharmacokinetics of revefenacin and its major metabolite (THRX-195518) in patients with chronic obstructive pulmonary disease, and identify significant covariates affecting revefenacin disposition using a population pharmacokinetic approach based on plasma concentration-time data obtained after single- and repeated-dose once-daily administration in three phase II and two phase III studies. METHODS: Plasma concentrations of revefenacin and THRX-195518 following once-daily administration via nebulization at a dose levels ranging from 22-700 µg in 935 patients (488 men, 447 women; age 41-88 years) were analyzed using nonlinear mixed-effects modeling. RESULTS: Plasma revefenacin pharmacokinetics was best described by a two-compartment model with first-order absorption and elimination. Pharmacokinetic parameters for THRX-195518 were estimated using a sequential approach, where the concentration-time profiles were fit to a combined model. The formation of the metabolite in each subject was estimated to be a fixed fraction of the individually estimated (post-hoc) clearance rate of revefenacin. Four statistically significant covariates were identified: for revefenacin, age on apparent clearance and body weight on apparent intercompartment clearance, for THRX-195518, age on apparent clearance and body weight on the fraction of revefenacin apparent clearance that was metabolized to THRX-195518. CONCLUSIONS: None of the identified statistically significant covariates were associated with a clinically meaningful effect on revefenacin or THRX-195518 exposure in patients with chronic obstructive pulmonary disease. REGISTRATION: ClinicalTrials.gov identifier number NCT03064113, NCT01704404, NCT02040792, NCT02459080, and NCT02512510.

Safety, Pharmacokinetics, and Pharmacodynamics of TD-0714, a Novel Potent Neprilysin Inhibitor in Healthy Adult and Elderly Subjects.

TD-0714 is an orally active, potent, and selective inhibitor of human neprilysin (NEP) in development for the treatment of chronic heart failure. Oral administration of TD-0714 in rats resulted in dose-dependent and sustained increases in plasma cyclic guanosine monophosphate (cGMP) over 24 hours consistent with NEP target engagement. Randomized, double-blind, placebo controlled, single ascending dose (50-600 mg TD-0714) and multiple ascending dose (10-200 mg TD-0714 q.d. for 14 days) studies were conducted in healthy volunteers. TD-0714 was generally well-tolerated and no serious adverse events or clinically significant effects on vital signs or electrocardiogram parameters were observed. TD-0714 exhibited dose-proportional pharmacokinetics (PKs) with high oral bioavailability, minimal accumulation after once daily dosing, and negligible renal elimination. Pharmacodynamic (PD) responses were observed at all dose levels studied, as reflected by statistically significant increases in plasma cGMP concentrations. The increases in cGMP were significantly above the baseline (~ 50-100%) on day 14 for the entire 24-hour interval indicating that sustained cGMP elevations are achieved at steady-state. Maximal steady-state cGMP response was observed in plasma and urine at doses ≥ 50 mg. The TD-0714 PK-PD relationship and safety profile were similar in elderly vs. younger adult subjects. The TD-0714 PK and PD profiles support further clinical development of TD-0714 and suggest the potential for once-daily administration and predictable exposure in patients with cardiorenal diseases regardless of their renal function.

Tracheostomy during COVID-19 pandemic-Novel approach.

BACKGROUND: This study describes a novel approach in reducing SARS-CoV-2 transmission during tracheostomy. METHODS: Five patients underwent tracheostomy between April 1, 2020 and April 17, 2020. A clear and sterile plastic drape was used as an additional physical barrier against droplets and aerosols. Operative diagnosis; droplet count and distribution on plastic sheet and face shields were documented. RESULTS: Tracheostomy was performed for patients with carcinoma of tonsil (n = 2) and nasopharynx (n = 1), and aspiration pneumonia (n = 2). Droplet contamination was noted on all plastic sheets (n = 5). Droplet contamination was most severe over the central surface at 91.5% (86.7%-100.0%) followed by the left and right lateral surfaces at 5.2% (6.7%-10.0%) and 3.3% (6.7%-10.0%), respectively. No droplet contamination was noted on all face shields. CONCLUSION: Plastic drapes can help reduce viral transmission to health care providers during tracheostomy. Face shields may be spared which in turn helps to conserve resources during the novel coronavirus disease 2019 pandemic.

Pharmacokinetics and safety of revefenacin in subjects with impaired renal or hepatic function.

Purpose: Revefenacin, a long-acting muscarinic antagonist for nebulization, has been shown to improve lung function in patients with chronic obstructive pulmonary disease. Here we report pharmacokinetic (PK) and safety results from two multicenter, open-label, single-dose trials evaluating revefenacin in subjects with severe renal impairment (NCT02578082) and moderate hepatic impairment (NCT02581592). Subjects and methods: The renal impairment trial enrolled subjects with normal renal function and severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2). The hepatic impairment trial enrolled subjects with normal hepatic function and moderate hepatic impairment (Child-Pugh class B). Subjects received a single 175-µg dose of revefenacin through nebulization. PK plasma samples and urine collections were obtained at multiple time points for 5 days following treatment; all subjects were monitored for adverse events. Results: In the renal impairment study, the maximum observed plasma revefenacin concentration (Cmax) was up to 2.3-fold higher and area under the concentration-time curve from time 0 to infinity (AUCinf) was up to 2.4-fold higher in subjects with severe renal impairment compared with those with normal renal function. For THRX-195518, the major metabolite of revefenacin, the corresponding changes in Cmax and AUCinf were 1.8- and 2.7-fold higher, respectively. In the hepatic impairment study, revefenacin Cmax and AUCinf were 1.03- and 1.18-fold higher, respectively, in subjects with moderate hepatic impairment compared with those with normal hepatic function. The corresponding changes in THRX-195518 Cmax and AUCinf were 1.5- and 2.8-fold higher, respectively. Conclusion: Systemic exposure to revefenacin increased modestly in subjects with severe renal impairment but was similar between subjects with moderate hepatic impairment and normal hepatic function. The increase in plasma exposure to THRX-195518 in subjects with severe renal or moderate hepatic impairment is unlikely to be of clinical consequence given its low antimuscarinic potency, low systemic levels after inhaled revefenacin administration, and favorable safety profile.

Successful treatment of jellyfish sting-induced severe digital ischemia with intravenous iloprost infusion.

Jellyfish sting-induced vasospasm and vasculitis is a rare complication that could lead to severe digital ischemia and gangrene. We report a 39-year-old woman with severe pain in her right middle, ring, and little fingers after being stung by a jellyfish. Therapy was initiated with a course of intravenous iloprost infusion and subcutaneous low-molecular-weight heparin, with successful revascularization. Our case illustrates that although emergency transfer to a vascular center is ideal, even in a delayed setting, patients can still benefit from specialist vascular care with a combination of medication and iloprost treatment, with acceptable functional outcome.

A model-based approach to investigating the pathophysiological mechanisms of hypertension and response to antihypertensive therapies: extending the Guyton model.

Reproducibly differential responses to different classes of antihypertensive agents are observed among hypertensive patients and may be due to interindividual differences in hypertension pathology. Computational models provide a tool for investigating the impact of underlying disease mechanisms on the response to antihypertensive therapies with different mechanisms of action. We present the development, calibration, validation, and application of an extension of the Guyton/Karaaslan model of blood pressure regulation. The model incorporates a detailed submodel of the renin-angiotensin-aldosterone system (RAAS), allowing therapies that target different parts of this pathway to be distinguished. Literature data on RAAS biomarker and blood pressure responses to different classes of therapies were used to refine the physiological actions of ANG II and aldosterone on renin secretion, renal vascular resistance, and sodium reabsorption. The calibrated model was able to accurately reproduce the RAAS biomarker and blood pressure responses to combinations of dual-RAAS agents, as well as RAAS therapies in combination with diuretics or calcium channel blockers. The final model was used to explore the impact of underlying mechanisms of hypertension on the blood pressure response to different classes of antihypertensive agents. Simulations indicate that the underlying etiology of hypertension can impact the magnitude of response to a given class of therapy, making a patient more sensitive to one class and less sensitive others. Given that hypertension is usually the result of multiple mechanisms, rather than a single factor, these findings yield insight into why combination therapy is often required to adequately control blood pressure.

Integration of biostatistics and pharmacometrics computing platforms for efficient and reproducible PK/PD analysis: a case study.

Results of pharmacometric analyses influence high-level decisions such as clinical trial design, drug approval, and labeling. Key challenges for timely delivery of pharmacometric analyses are the data assembly process and tracking and documenting the modeling process and results. Since clinical efficacy and safety data typically reside in the biostatistics computing area, an integrated computing platform for pharmacometric and biostatistical analyses would be ideal. A case study is presented integrating a pharmacometric modeling platform into an existing statistical computing environment (SCE). The feasibility and specific configurations of running common PK/PD programs such as NONMEM and R inside of the SCE are provided. The case study provides an example of an integrated repository that facilitates efficient data assembly for pharmacometrics analyses. The proposed platform encourages a good pharmacometrics working practice to maintain transparency, traceability, and reproducibility of PK/PD models and associated data in supporting drug development and regulatory decisions.

Modeling hepatitis C virus dynamics: liver regeneration and critical drug efficacy.

Mathematical models for hepatitis C viral (HCV) RNA kinetics have provided a means of evaluating the antiviral effectiveness of therapy, of estimating parameters such as the rate of HCV RNA clearance, and they have suggested mechanism of action against HCV for both interferon and ribavirin. Nevertheless, the model that was originally formulated by Neumann et al. [1998. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science 282 (5386), 103-107] is unable to explain all of the observed HCV RNA profiles under treatment e.g., a triphasic viral decay and a viral rebound to baseline values after the cessation of therapy. Further, the half-life of productively HCV-infected cells, estimated from the second phase HCV RNA decline slope, is very variable and sometimes zero with no clear understanding of why. We show that extending the original model by including hepatocyte proliferation yields a more realistic model without any of these deficiencies. Further, we define and characterize a critical drug efficacy, such that for efficacies above the critical value HCV is ultimately cleared, while for efficacies below it, a new chronically infected viral steady-state level is reached.

Theoretical simulation of K(+)-based mechanisms for regulation of capillary perfusion in skeletal muscle.

Muscle fibers release K(+) into the interstitial space upon recruitment. Increased local interstitial K(+) concentration ([K(+)]) can cause dilation of terminal arterioles, leading to perfusion of downstream capillaries. The possibility that capillary perfusion can be regulated by vascular responses to [K(+)] was examined using a theoretical model. The model takes into account the spatial relationship between functional units of muscle fiber recruitment and capillary perfusion. Diffusion of K(+) in the interstitial space was simulated. Two hypothetical mechanisms for vascular sensing of interstitial [K(+)] were considered: direct sensing by arterioles and sensing by capillaries with stimulation of feeding arterioles via conducted responses. Control by arteriolar sensing led to poor tissue oxygenation at high levels of muscle activation. With control by capillary sensing, increases in perfusion matched increases in oxygen demand. The time course of perfusion after sudden muscle activation was considered. Predicted capillary perfusion increased rapidly within the first 5 s of muscle fiber activation. The reuptake of K(+) by muscle fibers had a minor effect on the increase of interstitial [K(+)]. Uptake by perfused capillaries was primarily responsible for limiting the increase in [K(+)] in the interstitial space at the onset of fiber activation. Vascular responses to increasing interstitial [K(+)] may contribute to the rapid increase in blood flow that is observed to occur after the onset of muscle contraction.

Oxygen delivery to skeletal muscle fibers: effects of microvascular unit structure and control mechanisms.

The number of perfused capillaries in skeletal muscle varies with muscle activation. With increasing activation, muscle fibers are recruited as motor units consisting of widely dispersed fibers, whereas capillaries are recruited as groups called microvascular units (MVUs) that supply several adjacent fibers. In this study, a theoretical model was used to examine the consequences of this spatial mismatch between the functional units of muscle activation and capillary perfusion. Diffusive oxygen transport was simulated in cross sections of skeletal muscle, including several MVUs and fibers from several motor units. Four alternative hypothetical mechanisms controlling capillary perfusion were considered. First, all capillaries adjacent to active fibers are perfused. Second, all MVUs containing capillaries adjacent to active fibers are perfused. Third, each MVU is perfused whenever oxygen levels at its feed arteriole fall below a threshold value. Fourth, each MVU is perfused whenever the average oxygen level at its capillaries falls below a threshold value. For each mechanism, the dependence of the fraction of perfused capillaries on the level of muscle activation was predicted. Comparison of the results led to the following conclusions. Control of perfusion by MVUs increases the fraction of perfused capillaries relative to control by individual capillaries. Control by arteriolar oxygen sensing leads to poor control of tissue oxygenation at high levels of muscle activation. Control of MVU perfusion by capillary oxygen sensing permits adequate tissue oxygenation over the full range of activation without resulting in perfusion of all MVUs containing capillaries adjacent to active fibers.

Dynamics of hepatitis B virus infection.

Mathematical models of the dynamics of HIV and hepatitis C virus infection have proven to be of great utility in understanding pathogenesis and designing better treatments. Here, we review the state of the art in modeling and interpreting data obtained from hepatitis B virus infected patients treated with antiviral agents.