Simulation summary
90% model interval: the 5th–95th percentile of simulated parameter outcomes. “Unfitted” means no measured drug concentrations were used to update the model; “updated” means observations were used for Bayesian reweighting. Neither establishes 90% accuracy in clinical patients. Use Model validation to check held-out measurements.
Compare modes on the same graph
Choose overlays. Custom sequence represents one patient switching modalities; the other curves are separate counterfactual scenarios. Dialysis shading follows the primary scenario so windows do not become visually ambiguous.
IV acyclovir administration Oral valacyclovir administration (vertical dashed lines)
Plasma acyclovir
No validated therapeutic or toxic plasma acyclovir concentration has been established. Published steady-state IV peak and trough values are presented in Drug references [10].
CSF acyclovir
No validated CSF acyclovir therapeutic threshold is established. The optional shaded IC₅₀ range represents cell-culture susceptibility, not a CNS efficacy target [11].
Residual kidney-only acyclovir clearance
With CrCl = 0 mL/min, the model sets acyclovir renal clearance and CMMG renal clearance to exactly zero. The independent metabolism and dialysis terms are not set to zero. Renal clearance per unit of CrCl is an exploratory model assumption, not a validated patient-specific estimate. [1]
Dialysis-only acyclovir clearance
Net dialysis transfer is zero outside active HD, PD dwells, and CRRT. The peritoneal transfer component may be negative during back-diffusion. Colored comparison lines can remain above zero if other scenarios with active dialysis are overlaid. [1][2]
Total acyclovir clearance (including the patient's kidneys)
Displayed instantaneous net elimination = residual kidney + nonrenal/metabolic + net dialysis transfer. During PD, net drug back-diffusion can reduce apparent total elimination. It normally remains above zero when dialysis is off because the body still eliminates some acyclovir.
Dialysis drug removal / peritoneal transfer
Membrane transfer rate is zero outside dialysis windows; PD mass is counted as removed only after a drain. Back-diffusion can make net transfer negative during a dwell. Urea Kt/V is not substituted for acyclovir clearance [1][2].
Peritoneal dialysis membrane transport
Model-predicted net ultrafiltration and dialysate acyclovir, reflecting glucose gradient decay, membrane transport and completed drains. This is a simplified mass-balance teaching model, not a validated three-pore model. [12]
Net ultrafiltration rate (mL/hour)
Dialysate acyclovir concentration (mg/L)
Dialysis sessions
Applies dialysis windows and PD exchanges together; custom medication doses are applied if edited. Otherwise the repeating dose regimen remains in effect.
Enter exact treatment times from the beginning of the simulation. For example, HD from 18 to 24 hours, or PD from 0–24 followed by HD from 30–34. Sequential HD, PD, and CRRT treatments are allowed; simultaneous modalities are not modeled.
Timeline preview
Individual PD exchange prescription
This table supports separate prescriptions for each custom PD window. Select a specific PD session or “Each PD window” for a repeated template. Exchange start times are offsets in hours from the start of that PD session, not absolute simulation hours. Apply the custom timeline to commit medication doses, dialysis windows and PD exchanges together. Measured net UF is optional; if provided, the model uses it as the net fluid-volume change over the dwell. It does not establish measured acyclovir transport or membrane sieving.
| # | PD session | Offset (h) | Dwell (h) | Fill (L) | Dextrose (%) | Net UF (mL, optional) |
|---|
For cycler PD, start times are relative to cycler treatment start and can include turnover gaps. The table repeats with each PD session. Dialysate solute transfer remains a research approximation; observed net UF constrains water balance, not acyclovir clearance. [12]
Medication administration schedule
Enter the exact hour from the beginning of the simulation for each administration, its route and amount. Example: 1,000 mg oral valacyclovir at hour 12, followed by 250 mg IV acyclovir at hours 24 and 48. Oral and IV drugs become acyclovir in the same central and peripheral compartments; the predicted plasma, CSF and CMMG levels carry forward across doses and dialysis transitions.
Medication administration timeline
Bayesian model updating & 90% interval coverage
How it works: Enter actual assay measurements from the same dosing and dialysis scenario. Rows marked Fit update the relative probabilities of the model's sampled parameter sets using a Gaussian assay-error assumption. Hold-out rows are never used for fitting and test whether the 90% posterior predictive interval contains each observed value. The posterior is an importance-sampling approximation, not a clinically validated population model. Do not enter identifiable patient information.
Change the primary dialysis scenario to change which prescription the measured values are compared with.
| Hour | Analyte | Observed (mg/L) | Role |
|---|
Assessment requires independent held-out measurements. Fitted data cannot validate coverage. With only a few hold-outs the coverage percentage is statistically unstable. An assay-error CV is assumed; the actual laboratory error structure may differ.
Why upper uncertainty bands can be wide
Small simulated clearance, high distribution volume, oral absorption variability, accumulated doses, and CSF/CMMG formation parameters produce right-skewed concentration distributions. A 5th–95th percentile band is not the same thing as ±10% error. If the effective sample size becomes very small, Bayesian reweighting is unreliable; acquire more observations or rerun a better-fitting model.
Antiviral activity and interpretation
Herpes simplex (HSV-1 and HSV-2) and varicella-zoster virus (VZV): Acyclovir is phosphorylated first by viral thymidine kinase and then by cellular enzymes to acyclovir triphosphate, which inhibits viral DNA polymerase and terminates viral DNA synthesis [11]. This simulator predicts acyclovir and CMMG concentrations; it does not simulate viral replication, intracellular acyclovir triphosphate, clinical response, or clearance of infection.
Laboratory susceptibility: Reported cell-culture IC₅₀ ranges are HSV-1, 0.02–13.5 mg/L; HSV-2, 0.01–9.9 mg/L; and VZV, 0.12–10.8 mg/L [11]. The selected virus determines the optional laboratory susceptibility range. It does not change the modeled distribution or elimination of acyclovir. These ranges do not establish a therapeutic plasma or CSF target.
CNS infection: IV acyclovir is used in the treatment of HSV encephalitis and severe VZV disease according to indication-specific guidance. Dose, duration and renal adjustment depend on the clinical context; oral valacyclovir predictions should not be interpreted as evidence of equivalence to IV therapy in encephalitis [9] [14].
Half-life and concentration references
| Measure | Published figure | Meaning |
|---|---|---|
| Acyclovir elimination half-life, normal kidney function | 2.5–3.3 hours [11] | Typical population values, not a patient-specific prediction. |
| Acyclovir terminal half-life, anuric off HD | 19.5 ± 5.9 hours [1] | Small historical study (n=6). |
| Acyclovir half-life during HD | 5.7 ± 0.85 hours [1] | Measured during a historical 6-hour HD session; not universal with modern membranes. |
| Acyclovir plasma concentrations during IV treatment | 10 mg/kg IV every 8 hours (1-hour infusions; n=7): mean steady-state peak 22.9 mg/L, trough 1.9 mg/L [10] | Regimen-specific observed plasma concentrations in adults with normal renal function; not therapeutic or toxic thresholds. |
| Plasma/CSF levels in CNS-infection cohort | Median serum 3.27 mg/L and CSF 1.96 mg/L (converted from µmol/L) [4] | Small observational cohort with variable sampling times; neither value is a therapeutic or toxic threshold. |
| CMMG neurotoxicity-associated plasma concentration | 10.8 µmol/L ≈ 2.58 mg/L [3] | Study-derived discriminating level, not a universal toxic cutoff. |
| Acyclovir IC₅₀ in HSV-1, HSV-2, and VZV cell-culture assays | HSV-1: 0.02–13.5; HSV-2: 0.01–9.9; VZV: 0.12–10.8 mg/L [11] | Laboratory susceptibility only; no validated plasma or CSF efficacy target. |
Therapeutic concentrations: No validated plasma or CSF target concentration has been established for HSV or VZV CNS infection. Neurotoxicity: CMMG 2.58 mg/L (10.8 µmol/L) is an observational risk-associated concentration, not an absolute diagnostic threshold [3].
Compare modeled outcomes
Acyclovir removed by dialysis (mg): cumulative acyclovir mass extracted by HD/CRRT plus acyclovir recovered in drained peritoneal dialysate during the modeled time period. This excludes renal and nonrenal elimination, and drug remaining in an undrained PD dwell. It is not a percentage of the administered dose or a measure of total body clearance. PD recovery is based on an unvalidated prescription-level transport model.
Model definitions and evidence
Acyclovir (whether administered IV or generated from oral valacyclovir) is represented with a two-compartment plasma/peripheral distribution model, separate exploratory CSF effect compartments, and a formed CMMG compartment. Residual renal clearance and time-dependent dialysis clearance act on circulating drug. The model uses representative literature dialysis values as anchors, but most remaining parameters have not been estimated from patient-level data in an externally validated population PK model [1][2].
Zero residual kidney function: both the acyclovir and CMMG renal elimination terms are multiplied by CrCl and are exactly zero at CrCl 0 mL/min, including every Monte Carlo draw. Nonrenal metabolism and active dialysis clearance remain separate, and may stay positive. The plotted renal-only clearance is separate from total drug clearance. This mathematical property is not a verified estimate of all clearance pathways in an individual patient.
Medication schedules: The repeating regimen generates no more than the selected total number of administrations, beginning at hour 0 and spaced by the chosen interval. Administrations scheduled beyond the displayed horizon are not simulated. The custom medication timeline supports a sequence of oral valacyclovir and IV acyclovir administrations at specific hours; an IV dose is a timed infusion, while oral valacyclovir enters a first-order absorption depot. The same plasma, peripheral, CSF and CMMG amounts persist across administration-route changes and dialysis modalities. Adding or changing medication routes does not reset drug concentrations. Oral and IV dose milligram strengths must not be treated as interchangeable. This is an exploratory mathematical implementation and should not be used for clinical dosing [8] [9].
Oral valacyclovir: tablets are represented with a simplified first-order oral depot followed by rapid conversion to acyclovir. The active plasma drug is acyclovir, and CMMG is formed from it. The assumed fraction of acyclovir entering circulation after valacyclovir is 0.545, anchored to the US label's healthy-volunteer 1-g study. Dose strengths are valacyclovir free-base milligrams; conversion uses the free-base molecular-weight ratio 225.21/324.34. Absorption-rate and relative bioavailability distributions are illustrative rather than fitted; the label notes less-than-dose-proportional exposure across 250–1000 mg [8]. For exploratory input, oral valacyclovir accepts up to 6,000 mg per administration; this is not a dose recommendation. For >1,000 mg, the simplified constant-bioavailability model extrapolates beyond its anchor and may overestimate exposure due to nonlinear absorption. These oral predictions must not be used to replace IV treatment for suspected HSV or VZV encephalitis [9].
HD: an illustrative dialytic clearance anchored to the mean 81.8 mL/min in a small 1982 study [1]. PD: the historical CAPD study reported 3.4 mL/min measured total peritoneal clearance [2]. The simulator now uses a separate assumed membrane transfer coefficient, integrates diffusive and small-pore convective acyclovir transfer into a dialysate drug-mass compartment, tracks fluid volume and drains at exchange boundaries. Glucose concentration changes a simplified time-decaying osmotic ultrafiltration term; aquaporin water-only transport does not directly carry acyclovir. The illustrative transport, glucose-decay, reabsorption and reflection parameters are not fitted to drug concentrations [12]. Dialysate-associated drug is counted as removed when drained, not automatically at the time of membrane transfer. CMMG PD elimination remains a separate exploratory approximation.
Cockcroft–Gault CrCl: Estimated CrCl (mL/min) = (140 − age) × actual weight (kg) × sex coefficient / [72 × serum creatinine (mg/dL)]; sex coefficient 1.0 for male or 0.85 for female. Creatinine-based estimates are unreliable with unstable kidney function, dialysis, or atypical muscle mass; measured residual clearance may be preferred [13].
Time limits: each user-entered interval is at most 24 hours; ongoing PD or CRRT is entered as successive daily intervals. No treatment overlap is allowed. Residual CrCl is expressed in absolute mL/min. When Cockcroft–Gault is selected, the sex coefficient and actual body weight are used for estimation. The concentration bands are prior parameter ranges, or posterior-weighted parameter ranges after optional measurement fitting, and are not established clinical prediction errors.
CNS: plasma–CSF exchange and CMMG entry are a lagged partition approximation, not a physiologically based permeability model. CNS drug concentrations, viral susceptibility, and neurotoxicity markers should not be used to identify a suitable patient dose [3][4][5].
Model half-life: A single half-life is not displayed in the modality comparison because dynamic dialysis schedules do not have a single meaningful elimination half-life. The comparison instead reports the predicted plasma concentration at the end of the simulation. The model may internally calculate an off-dialysis terminal eigenvalue for research diagnostics, but this is not a validated clinical half-life. Published observed half-lives are listed under Drug references.
Bayesian 90% bands: The implementation uses weighted importance sampling of 120 default parameter draws. Entered fit measurements update each draw by a Gaussian likelihood (assay CV adjustable in Advanced Settings), and a separate held-out measurement is compared with the 90% posterior predictive range including assumed measurement error. Posterior parameter intervals and predictive intervals are different. Uncalibrated assumed priors and small effective sample sizes limit validity; there is no claim of 90% real-world coverage without external measured data.
Version 13 research tools: A prescription table can provide exchange-specific dwell, fill, dextrose, and optional net ultrafiltration. This constrains a simplified PD fluid and drug mass-balance model, not a clinically validated solute transport model. Model fitting uses aggregate label peak/trough concentrations for a nominal 70-kg adult with manually assumed CrCl 95 mL/min; fitting is neither a patient-level estimate nor independent validation. One-at-a-time sensitivity calculations use ±20% parameter perturbations. JSON configurations remain local to the browser.
Publications & source keys
- Laskin OL, et al. (1982). Acyclovir kinetics in end-stage renal disease. Two-compartment kinetics and HD clearance.
- Burgess ED, Gill MJ (1990). Intraperitoneal administration of acyclovir in CAPD. Measured peritoneal clearance.
- Helldén A, et al. (2003). Plasma CMMG and acyclovir-associated neuropsychiatric symptoms. Observational threshold.
- Lindström J, et al. (2019). CNS acyclovir, CMMG and neurological symptoms. CSF and serum observations and barrier effects.
- US acyclovir oral labeling. VZV in-vitro IC₅₀ range and important exposure limitations.
- Boelaert J, et al. (1987). Multiple-dose acyclovir PK in CAPD. Illustrates limitations of smaller compartment models.
- ISPD practice guidelines and resources. PD prescription dimensions including modality, dwell/exchange parameters and dialysate solutions.
- VALTREX prescribing information, clinical pharmacology. Valacyclovir is rapidly converted to acyclovir; reported mean absolute acyclovir bioavailability 54.5% ± 9.1% after 1 g oral dose; tablets labeled in valacyclovir free-base equivalents; oral exposure is not strictly dose proportional.
- NIH VZV guidance for adults and adolescents with HIV. Illustrates separate indications for oral antivirals in localized zoster versus IV acyclovir in severe/complicated infections.
- Acyclovir injection prescribing information: normal half-life, steady-state peak and trough, renal impairment.
- Oral acyclovir prescribing information: HSV-1, HSV-2, and VZV in-vitro IC₅₀ ranges, antiviral mechanism, and absence of a validated susceptibility-to-outcome relationship.
- Morelle J, et al. (2021). ISPD peritoneal membrane dysfunction recommendations: osmosis, small-solute transport, glucose gradient and ultrafiltration. Values used in this website's PD transport submodel are exploratory, not fit to an acyclovir APD dataset.
- National Kidney Foundation: Cockcroft–Gault equation and limitations. Historical CrCl estimator; accuracy varies with body composition, age and creatinine kinetics.
- NIH HSV adult/adolescent opportunistic infection guidelines: HSV CNS infection management and distinction between IV and oral antiviral regimens.
This simulator is for model comparison and teaching. An optional finite-ensemble Bayesian reweighting tool accepts investigator-entered concentrations, but no real patient data are supplied, and no independent external clinical validation has been performed. Oral valacyclovir results have not been validated for CNS treatment decisions.
Save / load a simulation
Export or import a local JSON configuration, including patient assumptions, dosing, dialysis schedules, exchange prescriptions, and model parameters. No information is sent to a server. Do not store identifiable patient data.
Published concentration benchmark
Compare a deterministic nominal adult simulation against the US IV acyclovir label's aggregate steady-state plasma concentrations, from 1-hour infusions every 8 hours. The label gives group means for 5 mg/kg (n=8) and 10 mg/kg (n=7), but not individual renal function or body weight. This is a model benchmark, not a matched clinical validation. [10]
| Regimen | Label peak / trough (mg/L) | Model peak / trough (mg/L) | Peak / trough bias (%) | Subjects |
|---|
Historical anuric benchmark (not fitted)
Laskin et al. (1982): six anuric HD patients received a single 2.5 mg/kg IV infusion over 1 hour, with measurements before dialysis. Literature mean ± SD values are converted from µmol/L to mg/L using acyclovir molecular weight 225.21 g/mol. Model assumptions: 70 kg, CrCl 0 mL/min, no HD during the first 24 hours. Timing and weight are nominal approximations, not patient-matched data. [1]
| Time from infusion start | Published mean ± SD (mg/L) | Model (mg/L) | Relative difference |
|---|
Fitting minimizes squared log errors for group mean peaks/troughs by adjusting central distribution volume and renal/nonrenal plasma clearance. The model cannot perfectly reproduce all published group means by a two-parameter linear fit. This is calibration against the same summary statistics shown above—not external validation, and not supported for individualized or dialysis prescribing.
One-at-a-time sensitivity analysis
Quantifies the influence of selected assumptions on drug exposure. The table shows percentage change in an output when the input is decreased by 20% / increased by 20%. Results use nominal parameter values, not fitted or posterior uncertainty bands.
| Parameter | Plasma AUC | Peak CSF acyclovir | Peak plasma CMMG | Dialysis removal |
|---|
AyFlux license — GNU AGPLv3
CloseAyFlux source code is distributed under the GNU Affero General Public License, version 3. Existing third-party components, including Plotly, retain their own licenses. See the included THIRD_PARTY_NOTICES.md in the hosting ZIP.
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Termination of your rights under this section does not terminate the
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Notwithstanding any other provision of this License, if you modify the
Program, your modified version must prominently offer all users
interacting with it remotely through a computer network (if your version
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of the GNU General Public License that is incorporated pursuant to the
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If the disclaimer of warranty and limitation of liability provided
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END OF TERMS AND CONDITIONS
How to Apply These Terms to Your New Programs
If you develop a new program, and you want it to be of the greatest
possible use to the public, the best way to achieve this is to make it
free software which everyone can redistribute and change under these terms.
To do so, attach the following notices to the program. It is safest
to attach them to the start of each source file to most effectively
state the exclusion of warranty; and each file should have at least
the "copyright" line and a pointer to where the full notice is found.
<one line to give the program's name and a brief idea of what it does.>
Copyright (C) <year> <name of author>
This program is free software: you can redistribute it and/or modify
it under the terms of the GNU Affero General Public License as published by
the Free Software Foundation, either version 3 of the License, or
(at your option) any later version.
This program is distributed in the hope that it will be useful,
but WITHOUT ANY WARRANTY; without even the implied warranty of
MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the
GNU Affero General Public License for more details.
You should have received a copy of the GNU Affero General Public License
along with this program. If not, see <https://www.gnu.org/licenses/>.
Also add information on how to contact you by electronic and paper mail.
If your software can interact with users remotely through a computer
network, you should also make sure that it provides a way for users to
get its source. For example, if your program is a web application, its
interface could display a "Source" link that leads users to an archive
of the code. There are many ways you could offer source, and different
solutions will be better for different programs; see section 13 for the
specific requirements.
You should also get your employer (if you work as a programmer) or school,
if any, to sign a "copyright disclaimer" for the program, if necessary.
For more information on this, and how to apply and follow the GNU AGPL, see
<https://www.gnu.org/licenses/>.
Cite AyFlux
CloseSuggested software citation metadata (CITATION.cff):
cff-version: 1.2.0
message: "If you use AyFlux in research, cite this software and the original pharmacokinetic studies referenced in the Methods section."
title: "AyFlux: Acyclovir Pharmacokinetics Simulator"
type: software
authors:
- family-names: Khalil
given-names: Muhammad
version: "0.16.0"
license: AGPL-3.0-only
repository-code: "https://github.com/khalilm3264/acyclovirpksim"
keywords:
- acyclovir
- pharmacokinetics
- hemodialysis
- peritoneal dialysis
- renal replacement therapy
- Monte Carlo
Use a versioned release citation when available. The citation file is also included in the hosting ZIP.